Medical device rapid drug releasing coatings comprising a therapeutic agent and a contrast agent

ABSTRACT

The invention relates to a coated medical device for rapid delivery of a therapeutic agent to a tissue in seconds to minutes. The medical device has a layer overlying the exterior surface of the medical device. The layer contains a therapeutic agent, a contrast agent, and an additive.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.11/942,452, filed Nov. 19, 2007, which claims the benefit of priority ofU.S. Provisional Application No. 60/860,084, filed on Nov. 20, 2006,U.S. Provisional Application No. 60/880,742, filed Jan. 17, 2007, U.S.Provisional Application No. 60/897,427, filed on Jan. 25, 2007, U.S.Provisional Application No. 60/903,529 filed on Feb. 26, 2007, U.S.Provisional Application No. 60/904,473 filed Mar. 2, 2007, U.S.Provisional Application No. 60/926,850 filed Apr. 30, 2007, U.S.Provisional Application No. 60/981,380 filed Oct. 19, 2007, and U.S.Provisional Application No. 60/981,384 filed Oct. 19, 2007, thedisclosures of all of which are incorporated by reference herein.

FIELD OF THE INVENTION

Embodiments of the present invention relate to coated medical devices,and particularly to coated balloon catheters, and their use for rapidlydelivering a therapeutic agent to particular tissue or body lumen, fortreatment of disease and particularly for reducing stenosis and latelumen loss of a body lumen. Embodiments of the present invention alsorelate to methods of manufacturing these medical devices, the drugreleasing coatings of therapeutic agent and contrast agent provided onthese medical devices, the solutions for making those coatings, andmethods for treating a body lumen such as the vasculature, includingparticularly arterial vasculature, for example, using these coatedmedical devices.

BACKGROUND OF THE INVENTION

It has become increasingly common to treat a variety of medicalconditions by introducing a medical device into the vascular system orother lumen within a human or veterinary patient such as the esophagus,trachea, colon, biliary tract, or urinary tract. For example, medicaldevices used for the treatment of vascular disease include stents,catheters, balloon catheters, guide wires, cannulas and the like. Whilethese medical devices initially appear successful, the benefits areoften compromised by the occurrence of complications, such as latethrombosis, or recurrence of disease, such as stenosis (restenosis),after such treatment.

Restenosis, for example, involves a physiological response to thevascular injury caused by angioplasty. Over time, de-endotheliazationand injury to smooth muscle cells results in thrombus deposition,leukocyte and macrophage infiltration, smooth muscle cellproliferation/migration, fibrosis and extracellular matrix deposition.Inflammation plays a pivotal role linking early vascular injury to theeventual consequence of neointimal growth and lumen compromise. Inballoon-injured arteries, leukocyte recruitment is confined to earlyneutrophil infiltration, while in stented arteries, early neutrophilrecruitment is followed by prolonged macrophage accumulation. Thewidespread use of coronary stents has altered the vascular response toinjury by causing a more intense and prolonged inflammatory state, dueto chronic irritation from the implanted foreign body, and in the caseof drug eluting stents (DES), from insufficient biocompatibility of thepolymer coating.

Over the past several years, numerous local drug delivery systems havebeen developed for the treatment and/or the prevention of restenosisafter balloon angioplasty or stenting. Examples include local drugdelivery catheters, delivery balloon catheters, and polymeric drugcoated stents. Given that many diseases affect a specific local site ororgan within the body, it is advantageous to preferentially treat onlythe affected area. This avoids high systemic drug levels, which mayresult in adverse side effects, and concentrates therapeutic agents inthe local area where they are needed. By treating just the diseasedtissue, the total quantity of drug used may be significantly reduced.Moreover, local drug delivery may allow for the use of certain effectivetherapeutic agents, which have previously been considered too toxic ornon-specific to use systemically.

One example of a local delivery system is a drug eluting stent (DES).The stent is coated with a polymer into which drug is impregnated. Whenthe stent is inserted into a blood vessel, the polymer degrades and thedrug is slowly released. The slow release of the drug, which takes placeover a period of weeks to months, has been reported as one of the mainadvantages of using DES. However, while slow release may be advantageousin the case where a foreign body, such as a stent, is deployed, which isa source of chronic irritation and inflammation, if a foreign body isnot implanted it is instead advantageous to rapidly deliver drug to thevascular tissue at the time of treatment to inhibit inflammation andcellular proliferation following acute injury. Thus, a considerabledisadvantage of a DES, or any other implanted medical device designedfor sustained release of a drug, is that the drug is incapable of beingrapidly released into the vessel.

Additionally, while drug-eluting stents were initially shown to be aneffective technique for reducing and preventing restenosis, recentlytheir efficacy and safety have been questioned. A life-threateningcomplication of the technology, late thrombosis, has emerged as a majorconcern. Drug eluting stents cause substantial impairment of arterialhealing, characterized by a lack of complete re-endothelialization and apersistence of fibrin when compared to bare metal stents (BMS), which isunderstood to be the underlying cause of late DES thrombosis. Concernshave also been raised that the polymeric matrix on the stent in whichthe anti-proliferative drug is embedded might exacerbate inflammationand thrombosis, since the polymers used are not sufficientlybiocompatible. These polymeric systems are designed to facilitatelong-term sustained release of drug over a period of days, months, oryears, not over a period of seconds or minutes. These polymeric drugcoatings of medical devices do not release the polymer, which remains onthe device even after drug is released. Even if biodegradable polymersare used, polymer and drug are not released at the same time. Rapidrelease of drug, an intent of embodiments of the present invention, fromthese polymeric systems is not possible. Thus, combining a therapeuticagent with a polymer in a medical device coating may have significantdisadvantages.

Another important limitation of the DES is that the water insolubledrugs are not evenly distributed in the polymeric matrix of the coating.Furthermore, drug and polymer are concentrated on the struts of thestent, but not in gaps between the struts. The non-uniform distributionof drug causes non-uniform drug release to the tissue of the vesselwalls. This may cause tissue damage and thrombosis in areas exposed toexcess drug and hyperplasia and restenosis areas that are undertreated.Thus, there is a need to improve the uniformity of drug delivery totarget tissues by improving drug solubility in coatings of medicaldevices by increasing the drug's compatibility with carriers in thecoatings, such as a polymeric matrix, thereby eliminating or reducingthe size of drug crystal particles in the polymeric matrix or othercoating to create a uniform drug distribution in the drug coating on themedical device.

Yet another important limitation of the DES is that only a limitedamount of an active agent can be loaded into the relatively smallsurface area of the stent.

Non-stent based local delivery systems, such as balloon catheters, havealso been effective in the treatment and prevention of restenosis. Theballoon is coated with an active agent, and when the blood vessel isdilated, the balloon is pressed against the vessel wall to deliver theactive agent. Thus, when balloon catheters are used, it is advantageousfor the drug in the coating to be rapidly released and absorbed by bloodvessel tissues. Any component of the coating that inhibits rapidrelease, such as a crosslinked polymer, liposome, or encapsulatingparticle, is necessarily disadvantageous to the intended use of theballoon catheter, which is inflated for a very brief period of time andthen removed from the body.

Hydrophilic drugs, such as heparin, have been reported to be deliverableby polymeric hydrogel coated balloon catheters. However, a polymerichydrogel coating can not effectively deliver water insoluble drugs (suchas paclitaxel and rapamycin), because they can not mix with the hydrogelcoating. Furthermore, the cross-linked polymeric hydrogel remains on theballoon after drug is released

Alternatively, balloon catheters are reported to have been coated withhydrophobic therapeutic agents that have been encapsulated in particlessuch as micelles, liposomes, nanoparticles or polymers. Liposomes, whichusually contain a core of aqueous solution, and micelles, which do not,have both been reported to be useful for pharmaceutical preparations ofwater-insoluble drugs for venous injection. However, for purposes of amedical device coating, all of these drug delivery formulations havesignificant disadvantages: drug loading is poor, and drug release fromthese preparations is slow.

Oils and lipids mix well with water-insoluble drugs such as paclitaxelor rapamycin, but when micelles or liposomes are then formed byinteraction with aqueous media, the particles and particle sizes arerelatively unstable, ranging in a broad particle size distribution fromseveral hundred nanometers to several microns in diameter. Severalreports suggest that the maximal concentration ratio of drug to lipidthat can be stably achieved in these particles is in the range of 0.2 to0.3; it is often less than 0.1.

Another disadvantage of oil-based liposome formulations is thedependence of drug absorption on the rate and extent of lipolysis.Lipolysis of oil-based triglycerides is difficult and dependent uponmany factors, and triglycerides must be digested and drug released inorder to be absorbed by diseased tissue. The amount of hydrophobic drugdelivered to tissues by these agents will be low, because liposomes andmicelles cannot efficiently release hydrophobic drug, which they carryaway before it can be absorbed by tissues. Micelles, liposomes, orparticles of oils and lipids are therefore not effective at rapidly andefficiently facilitating tissue uptake of drug during a very briefdevice deployment time, and no report has shown these types of coatingsto be effective.

Loading capacity of conventional micelles and liposomes is low. In theabsence of other considerations, the highest achievable drug to lipidratio is advantageous, since high lipid doses may raise concerns oftoxicitiy, and it is the drug—not the lipid—that provides thetherapeutic benefit, once it is delivered to target tissue. The ratio ofdrug to lipid in these formulations is often less than 0.1 and almostalways less than 0.2-0.3, because a significantly higher concentrationof lipid than drug is required in order for the drug to be encapsulatedin the particles, miscelles, or liposomes. Formulation stability ishighly dependent on drug-lipid interactions that are concentrationdependent. “In many studies, a maximum of 3 to 4 mol % drug (withrespect to phospholipid) possess stability of sufficient duration as tobe clinically useable. 8 mol % paclitaxel liposomes may be physicallystable for 15 min or less”—Preparation and Characterization ofTaxane-Containing Liposomes. Methods Enzymol. 2005; 391:97-117, p.101-2. Several attempts to achieve drug to lipid concentration ratioshigher than 0.2-0.3 failed (for example, see PDA J Pharm Sci Technol2006 60(3):144-55). These technologies involve forming the drug/lipidparticles first and then coating medical devices with the preparedparticles. Liposomes, for example, are prepared by first mixing drug andlipid in organic solvent, then removing the organic solvent to form alipid film or cake, then hydrating with aqueous solution and sonicating.

There are several reports showing that drug release from liposomal,miscellar, or particular oil/lipid formulations occurs very slowly, inthe range of days to weeks or months. In addition, the inventor hasfound that drug release occurs far too slowly from a coating consistingessentially of just oil/lipid and lipophilic drug, because they bind toeach other and to the external surface of the medical device so tightlythat the drug cannot rapidly elute off the device during several minutesor less of deployment at the target site. This slow-releasing propertyof prior approaches to drug:oil, drug:fatty acid, and drug:lipidformulations is not desirable in embodiments of the present inventions,wherein drug release takes place in the range of seconds to minutes.Thus the technology for oil/lipid formulation needs to be improvedsignificantly in order to be useful in the rapid drug release coatingsfor medical devices of the present invention.

Drug that is encapsulated in polymeric particles may take even longer todiffuse from the coating (the reported range is months to years) andwill have further difficulty permeating target tissues rapidly.Microspheres formed with polymeric materials, such as polyesters, whenused to encapsulate water insoluble drugs, are unable to release thedrug until the polymeric material is degraded. Thus, these polymericmicrospheres are useful for sustained release of drug over a long periodof time but cannot rapidly release drug and facilitate tissue uptake.

The iodine contrast agent iopromide has been used with paclitaxel tocoat balloon catheters and has had some variable success in thetreatment of restenosis. Notwithstanding this result, prior approachesto coating formulations with iodine contrast agent and a lipophilic orwater-insoluble therapeutic agent have serious drawbacks. The physicalcharacteristics of these coatings are very poor. There is a several-foldvariability in drug levels in tissue after treatment, which results ininconsistent therapeutic outcomes.

Experimentally, the present inventor has found that the compatability ormiscibility of lipophilic or water-insoluble therapeutic agents andiodine contrast agents is not good, and the integrity and uniformity ofthe coating is very poor. Particles from the coating easily flake offand are lost during handling. When the coating consists essentially ofiopromide and paclitaxel, for example, there is experimentallyseveral-fold variability in drug concentration distribution on thesurface of the medical device. Furthermore, there is marked variabilityin adhesion of drug to the surface of the device, and clumps of contrastagent and drug of variable size are formed that easily flake off thedevice during minimal handling in the interventional cardiology suite.These deficiencies adversely affect the consistency and uniformity ofdrug delivery to target tissues, which results in highly variable andinconsistent therapeutic effects and decreased therapeutic utility ofthe coated device. Improved coatings are therefore needed, coatings thatmaintain integrity during handling and more effectively and uniformlydeliver drug and facilitate its absorption by tissue.

Thus, the technology for formulating coatings of contrast agent and drugneeds to be improved significantly in order to achieve consistenttherapeutic results and to improve the clinical utility of the rapiddrug release coatings for medical devices.

Combining drugs and medical devices is a complicated area of technology.It involves the usual formulation challenges, such as those of oral orinjectable pharmaceuticals, together with the added challenge ofmaintaining drug adherence to the medical device until it reaches thetarget site and subsequently delivering the drug to the target tissueswith the desired release and absorption kinetics. Drug coatings ofmedical devices must also have properties such that they do not crackupon expansion and contraction of the device, for example, of a ballooncatheter or a stent. Furthermore, coatings must not impair functionalperformance such as burst pressure and compliance of balloons or theradial strength of self- or balloon-expanded stents. The coatingthickness must also be kept to a minimum, since a thick coating wouldincrease the medical device's profile and lead to poor trackability anddeliverability. These coatings generally contain almost no liquidchemicals, which typically are often used to stabilize drugs. Thus,formulations that are effective with pills or injectables might not workat all with coatings of medical device. If the drug releases from thedevice too easily, it may be lost during device delivery before it canbe deployed at the target site, or it may burst off the device duringthe initial phase of inflation and wash away before being pressed intocontact with target tissue of a body lumen wall. If the drug adheres toostrongly, the device may be withdrawn before the drug can be releasedand absorbed by tissues at the target tissues.

Thus, there is still a need to develop improved coatings of therapeuticagent and contrast agent for medical devices that rapidly, uniformly,and consistently deliver therapeutic agent directly into a localizedtissue area during or following a medical procedure, during a brief 0.1to 2 minute deployment of the device at the target site, so as to treator prevent vascular and nonvascular diseases such as stenosis. There isstill a need to develop coatings with improved compatability of contrastagent and lipophilic or water insoluble drug. There is still a need todevelop coatings that preserve coating integrity and uniformity of drugdistribution and that diminish the propensity for particles to flake offfrom the coating during handling. And there is still a need to developcoatings of contrast agent and drug that result in more uniform andconsistent delivery of drug to target tissue.

Thus, the technology for formulating medical device coatings of contrastagent and therapeutic agent needs to be improved significantly in orderto achieve consistent therapeutic results and to improve the clinicalutility of the coated medical devices, which is an object of embodimentsof the present invention.

SUMMARY OF THE INVENTION

The present inventor has found that coating the exterior surface of amedical device, and particularly of a balloon catheter or a stent, forexample, with a layer comprising a lipophilic or water-insolubletherapeutic agent, a contrast agent, and an additive that has both ahydrophilic part and a drug affinity part is useful in solving theproblems associated with the coatings discussed above. The drug affinitypart is a hydrophobic part and/or has an affinity to the therapeuticagent by hydrogen bonding and/or van der Waals interactions. Thehydrophilic part has a very good compatibility or miscibility with thehydrophilic contrast agent. In some embodiments, the additive includessurfactants. In embodiments of the present invention, the surfactant isan ionic or non-ionic surfactant. In another embodiment, the surfactantis an aliphatic or aromatic surfactant.

Surprisingly, the present inventor has found that the at least oneadditive according to embodiments of the present invention, whichcomprises a hydrophilic part and a drug affinity part, in combinationwith a lipophilic or water-insoluble therapeutic agent and a contrastagent, forms an effective drug delivery coating on a medical device thatavoids the disadvantages of conventional liposomal or encapsulationbased coating formulations such as slow release, lipolysis dependence,and a very low limit to drug:lipid concentration ratio. Moreover, thecoatings according to embodiments of the present invention avoid thedisadvantages of prior formulation technologies for coatings of contrastagent and lipophilic or water-insoluble drug, such as the inability topreserve coating integrity and uniformity of drug distribution, and theunavoidable flaking off of particles from the coating during handling.

The present inventor has also found that coating the exterior surface ofa medical device, and particularly of a balloon catheter or a stent, forexample, with a layer comprising a lipophilic or water-insolubletherapeutic agent, a contrast agent, and one of an oil, a fatty acid,and a lipid, wherein the therapeutic agent is not enclosed in liposomesor particles, is also useful in solving the problems associated with thecoatings discussed above.

The coatings according to embodiments of the present invention haveimproved resistance to mechanical disruption, improved preservation ofcoating integrity and uniformity of drug distribution, and diminishedpropensity for coating particles to flake off during handling of thedevice.

The coatings according to embodiments of the present invention alsofacilitate rapid, uniform, and consistent drug elution off of thesurface of the device and superior permeation of drug into tissues at adisease site to treat disease. For example, to treat stenosis and toreduce restenosis and late lumen loss of a body lumen. Thus, coatingsaccording to embodiments of the present invention provide an enhancedrate and/or consistency and/or uniformity and/or extent of absorption ofthe lipophilic or water-insoluble therapeutic agent in diseased tissuesof the vasculature or other body lumen.

In embodiments of the present invention, the coated device is forreducing stenosis and late lumen loss of a body lumen.

In embodiments of the present invention, the coated device improvesconsistency or decreases variability of drug uptake by tissue. Inembodiments of the present invention, the coated device improvesconsistency or decreases variability of the therapeutic outcome orclinical result of the treatment.

In one embodiment, the present invention relates to a medical device fordelivering a therapeutic agent to a tissue for reducing stenosis andlate lumen loss of a body lumen, the device comprising a layer overlyingan exterior surface of the medical device. The device includes one of aballoon catheter, a perfusion balloon catheter, an infusion cathetersuch as distal perforated drug infusion tube, a perforated balloon,spaced double balloon, porous balloon, and weeping balloon, a cuttingballoon catheter, a scoring balloon catheter, a laser catheter, anatherectomy device, a debulking catheter, a stent, a filter, a stentgraft, a covered stent, a patch, a wire, and a valve. Further, thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages.

In one embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, acontrast agent and an additive, wherein the contrast agent is chosenfrom iobitridol, iohexyl, iomeprol, iopamidol, iopentol, iopromide,ioversol, ioxilan, iotrolan, iodixanol, ioxaglate, and theirderivatives.

In one embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a lipophilic orwater-insoluble therapeutic agent, a contrast agent, and one of an oil,a fatty acid, and a lipid. In one embodiment, the therapeutic agent isnot encapsulated in liposomes or particles.

In one embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a lipophilic orwater-insoluble therapeutic agent, a contrast agent, and an additive,wherein the additive has both a hydrophilic part and a drug affinitypart, wherein the drug affinity part is at least one of a hydrophobicpart, a part that has affinity to the therapeutic agent by hydrogenbonding and/or charge and/or van der Waals interactions.

In one embodiment the present invention relates to a medical device fordelivering a therapeutic agent to a tissue, the device comprising alayer overlying the exterior surface of the medical device, the layercomprising a lipophilic or water-insoluble therapeutic agent, a contrastagent, and an additive, wherein the additive comprises a hydrophilicpart and a drug affinity part, wherein the drug affinity part is ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive iswater-soluble, and wherein the additive is at least one of a surfactantand a chemical compound. In one embodiment, the surfactant improvescompatibility and miscibility of the lipophilic or water-insoluble drugand the hydrophilic contrast agent. In one embodiment, the layeroverlying the exterior surface of the medical device consistsessentially of the therapeutic agent, the contrast agent, and theadditive.

In one embodiment, the layer overlying the exterior surface of themedical device includes the therapeutic agent, a contrast agent, and anadditive, but does not include a polymer.

In one embodiment, the additive in the layer comprising the therapeuticagent, a contrast agent, and an additive is an ionic or non-ionicsurfactant. In another embodiment, the additive is an aliphatic oraromatic surfactant. In another embodiment, the additive is a chemicalcompound with one or more hydroxyl, amino, carbonyl, carboxyl, acid,amide, ester moieties thereof.

In another embodiment, the additive is a chemical compound with one ormore hydroxyl, amino, carbonyl, carboxyl, acid, amide, or ester moietieswith a molecular weight of less than 5,000-10,000, preferably less than1000-5,000, more preferably less than 750-1,000, or most preferably lessthan 750. In this embodiment, molecular weight of the additive ispreferred to be less than that of the drug to be delivered. Smallmolecules can diffuse quickly, and they easily release from the surfaceof the delivery balloon, carrying drug with them. They quickly diffuseaway from drug when the drug binds tissue. The molecular weight of theadditives can not be too low, however; additives with molecular weightless than 80 are not desirable because they evaporate easily and are notstable components of the coating. In another embodiment, the additive ishydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxyl ester, orhydroxylamide. In another embodiment, the additive is gluconolactone orribonic acid lactone thereof. In yet another embodiment, the additive ischosen from meglumine/lactic acid, meglumine/gentisic acid,meglumine/acetic acid, lactobionic acid, Tween 20/sorbitol, Tween20/lactobionic acid, Tween 20/sugar or sugar derivatives. and N-octanoylN-methylglucamine. In another embodiment, the additive is a vitamin orderivative thereof. In another embodiment, the additive is an amino acidor derivative thereof. In another embodiment, the additive is a proteinor derivative thereof. In another embodiment, the additive is an albumin

In one embodiment, the layer overlying the exterior surface of themedical device does not include an oil, a lipid, or a polymer. Inanother embodiment, the layer overlying the exterior surface of themedical device does not include an oil. In another embodiment, the layeroverlying the exterior surface of the medical device does not include apolymer. In another embodiment, the layer overlying the exterior surfaceof the medical device does not include a purely hydrophobic additive. Inanother embodiment, the layer overlying the exterior surface of themedical device does not include salicylic acid or salts thereof. In yetanother embodiment, the layer overlying the exterior surface of themedical device does not include sodium salicylate.

In yet another embodiment, the layer overlying the exterior surface ofthe medical device does not include liposomes or encapsulatingparticles. In another embodiment, the layer overlying the exteriorsurface of the medical device includes one of an oil, fatty acid, andlipid.

In one embodiment, the additive in the layer comprising the therapeuticagent, the contrast agent and the additive is an ionic or non-ionicsurfactant. In another embodiment, the additive is an aliphatic oraromatic surfactant. In yet another embodiment, the additive is chosenfrom sorbitan oleate and sorbitan fatty esters.

In another embodiment, the additive is soluble in an aqueous solvent andis soluble in an organic solvent.

In one embodiment, the additive in the layer comprising the therapeuticagent, contrast agent and the additive is chosen from PEG fatty esters,PEG omega-3 fatty esters and alcohols, glycerol fatty esters, sorbitanfatty esters, PEG glyceryl fatty esters, PEG sorbitan fatty esters,sugar fatty esters, PEG sugar esters, vitamins and derivatives.

In one embodiment, the contrast agent in the layer overlying an exteriorsurface of the medical device is chosen from iobitridol, iohexyl,iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan, iotrolan,iodixanol, ioxaglate, and their derivatives. In one embodiment, thechemical compound in the layer overlying an exterior surface of themedical device is chosen from amino alcohols, hydroxyl carboxylic acid,ester, anhydrides, hydroxyl ketone, hydroxyl lactone, hydroxyl ester,sugar phosphate, sugar sulfate, ethyl oxide, ethyl glycols, amino acids,peptides, proteins, sorbitan, glycerol, polyalcohol, phosphates,sulfates, organic acids, esters, salts, vitamins, combinations of aminoalcohol and organic acid, and their substituted molecules. In oneembodiment, the surfactant in the layer overlying an exterior surface ofthe medical device is chosen from ionic, nonionic, aliphatic, andaromatic surfactants, PEG fatty esters, PEG omega-3 fatty esters, ether,and alcohols, glycerol fatty esters, sorbitan fatty esters, PEG glycerylfatty esters, PEG sorbitan fatty esters, sugar fatty esters, PEG sugaresters, and derivatives thereof.

In one embodiment, the chemical compound in the layer overlying anexterior surface of the medical device has one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups. In one aspect of thisembodiment, the chemical compound having one or more hydroxyl, amino,carbonyl, carboxyl, acid, amide or ester groups is chosen from aminoalcohols, hydroxyl carboxylic acid, ester, anhydrides, hydroxyl ketone,hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyloxide, ethyl glycols, amino acids, peptides, proteins, sorbitan,glycerol, polyalcohol, phosphates, sulfates, organic acids, esters,salts, vitamins, combinations of amino alcohol and organic acid, andtheir substituted molecules.

In another embodiment, the additive in the layer comprising thetherapeutic agent, the contrast agent, and the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In another embodiment, the additive in the layer comprising thetherapeutic agent, the contrast agent, and the additive is chosen fromTyloxapol, Octoxynol, oleth, laureth, PEG-glyceryl, monolaurate, PEG-20monolaurate, PEG 20 monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide.

In another embodiment, the additive in the layer comprising thetherapeutic agent, the contrast agent, and the additive is chosen frombenzalkonium chloride, benzethonium chloride, docecyl trimethyl ammoniumbromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,and dialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the therapeutic agent in the layer comprising thetherapeutic agent, the contrast agent, and the additive is one ofpaclitaxel and analogues thereof, rapamycin and analogues thereof,beta-lapachone and analogues thereof, biological vitamin D and analoguesthereof, and a mixture of these therapeutic agents. In anotherembodiment, the therapeutic agent is in combination with a secondtherapeutic agent, wherein the therapeutic agent is one of paclitaxel,rapamycin, and analogues thereof, and wherein the second therapeuticagent is one of beta-lapachone, biological active vitamin D, and theiranalogues. In one embodiment, the therapeutic agent is notwater-soluble.

In one embodiment, the additive enhances penetration and absorption ofthe therapeutic agent in tissue. In one embodiment, the additiveenhances release of the therapeutic agent off the medical device, andthe therapeutic agent, the contrast agent, and the additive arereleased. In another embodiment, the additive penetrates tissue, and thetherapeutic agent is not water soluble. In another embodiment, theadditive has water and alcohol solubility of at least 1 mg/ml and thetherapeutic agent is not water soluble.

In one embodiment, the concentration of the contrast agent and theadditive in the layer is from 1 to 20 μg/mm². The ratio of contrastagent to additive is in the range of 0.2-5.0. In one embodiment, theconcentration of the therapeutic agent in the layer is from 1 to 20μg/mm². In another embodiment, the concentration of the therapeuticagent in the layer is from 2 to 6 μg/mm².

In one embodiment of the medical device, the device is capable ofdelivering the therapeutic agent to the tissue in about 0.2 to 10minutes, or preferably from about 0.1 to 2 minutes. In anotherembodiment, the device is capable of delivering the therapeutic agent tothe tissue in about 0.1 to 1 minute.

In one embodiment, the medical device comprising a layer overlying anexterior surface of the medical device further comprises an adherentlayer between the exterior surface of the medical device and the layer.In another embodiment, the device further comprises a top layeroverlying the surface of the layer to reduce loss of drug during transitthrough a body to the tissue. In one embodiment, the top layer comprisesan additive that is less hydrophilic than the additive in the layeroverlying the exterior surface of the medical device, and wherein theadditive of the top layer is chosen from p-isononylphenoxypolyglycidol,PEG laurate, Tween 20, Tween 40, Tween 60, PEG oleate, PEG stearate, PEGglyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine; acetic anhydride, benzoic anhydride, ascorbic acid,2-pyrrolidone-5-carboxylic acid, sodium pyrrolidone carboxylate,ethylenediaminetetraacetic dianhydride, maleic and anhydride, succinicanhydride, diglycolic anhydride, glutaric anhydride, acetiamine,benfotiamine, pantothenic acid; cetotiamine; cyclothiamine,dexpanthenol, niacinamide, nicotinic acid, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof. Inanother embodiment, the medical device further comprises adimethylsulfoxide solvent layer, wherein the dimethylsulfoxide solventlayer is overlying the surface of the layer.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, acontrast agent, and at least two additives, wherein each of theadditives comprises a hydrophilic part and a drug affinity part, whereinthe drug affinity part is a hydrophobic part and/or has an affinity tothe therapeutic agent by hydrogen bonding and/or van der Waalsinteractions.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, acontrast agent, and an additive, wherein the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinitypart is a hydrophobic part and/or has an affinity to the therapeuticagent by hydrogen bonding and/or van der Waals interactions, wherein theadditive reduces crystal size and number of particles of the therapeuticagent, and wherein the therapeutic agent is not water soluble and is notenclosed in micelles or liposomes or encapsulated in polymer particles.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, acontrast agent and an additive, wherein the additive comprises ahydrophilic part and a drug affinity part, wherein the additive has afatty chain of an acid, ester, ether, or alcohol, wherein the fattychain directly inserts into lipid membrane structures of tissue, whereinthe additive has one or more functional groups which have affinity tothe drug by hydrogen bonding and/or van der Waals interactions (thefunctional groups include hydroxyl, ester, amide, carboxylic acid,primary, second, and tertiary amine, carbonyl, anhydrides, oxides, andamino alcohols), wherein the therapeutic agent is not water soluble andis not encapsulated in polymer particles, and wherein the layer does notinclude polymer.

In another embodiment of the medical device, the layer overlying theexterior surface of the medical device comprises a therapeutic agent, acontrast agent, and an additive, wherein the additive comprises ahydrophilic part and a drug affinity part, wherein the drug affinitypart is a hydrophobic part and/or has an affinity to the therapeuticagent by hydrogen bonding and/or van der Waals interactions, wherein theadditive is a surfactant and has a fatty chain of an acid, ester, ether,or alcohol, wherein the fatty chain directly inserts into the lipidmembrane structures of the tissue, and wherein the therapeutic agent isnot water soluble and is not encapsulated in polymer particles.

In another embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel forreducing stenosis and late lumen loss of body lumen, the cathetercomprising a coating layer overlying an exterior surface of a balloon.In one embodiment of the balloon catheter, the coating layer comprises atherapeutic agent, a contrast agent, and an additive, wherein theadditive comprises a hydrophilic part and a drug affinity part, whereinthe drug affinity part is at least one of a hydrophobic part, a partthat has an affinity to the therapeutic agent by hydrogen bonding, and apart that has an affinity to the therapeutic agent by van der Waalsinteractions, wherein the additive is water-soluble, and wherein theadditive is at least one of a surfactant and a chemical compound. In oneembodiment, the therapeutic agent is not encapsulated in polymerparticles. In one embodiment, the coating layer overlying an exteriorsurface of the exterior surface of the balloon catheter consistsessentially of the therapeutic agent, the contrast agent, and theadditive.

In one embodiment of the balloon catheter, the contrast agent in thecoating layer overlying an exterior surface of a balloon is chosen fromiobitridol, iohexyl, iomeprol, iopamidol, iopentol, iopromide, ioversol,ioxilan, iotrolan, iodixanol, ioxaglate, and their derivatives. In oneembodiment of the balloon catheter, the surfactant is chosen from ionic,nonionic, aliphatic, and aromatic surfactants, PEG fatty esters, PEGomega-3 fatty esters, ether, and alcohols, glycerol fatty esters,sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitan fattyesters, sugar fatty esters, PEG sugar esters, and derivatives thereof.In one embodiment, the chemical compound has one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups. In one aspect ofthis embodiment, the chemical compound having one or more hydroxyl,amino, carbonyl, carboxyl, acid, amide or ester groups is chosen fromamino alcohols, hydroxyl carboxylic acid, ester, and anhydrides,hydroxyl ketone, hydroxyl lactone, hydroxyl ester, sugar phosphate,sugar sulfate, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sorbitan, glycerol, polyalcohol, phosphates, sulfates, organicacids, esters, salts, vitamins, combinations of amino alcohol andorganic acid, and their substituted molecules.

In one embodiment of the balloon catheter, the additive in the coatinglayer is an ionic or non-ionic surfactant. In another embodiment, theadditive is a vitamin or derivative thereof. In another embodiment, theadditive is soluble in an aqueous solvent and is soluble in an organicsolvent. In yet another embodiment, the additive is chosen from sorbitanoleate and sorbitan fatty esters.

In one embodiment, the additive in the coating layer comprising thetherapeutic agent, the contrast agent, and the additive is chosen fromPEG fatty esters, PEG omega-3 fatty esters and alcohols, glycerol fattyesters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitanfatty esters, sugar fatty esters, PEG sugar esters, vitamins andderivatives.

In another embodiment, the additive in the coating layer comprising thetherapeutic agent, the contrast agent, and the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, Tween 20,Tween 40, Tween 60, Tween 80, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside,

In another embodiment, the additive in the coating layer comprising thetherapeutic agent, the contrast agent, and the additive is chosen fromTyloxapol, Octoxynol, oleth, laureth, PEG-glyceryl, monolaurate, PEG-20monolaurate, PEG 20 monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide.

In another embodiment, the additive in the coating layer comprising thetherapeutic agent, the contrast agent, and the additive is chosen frombenzalkonium chloride, benzethonium chloride, docecyl trimethyl ammoniumbromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,and dialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the therapeutic agent is one of paclitaxel andanalogues thereof, rapamycin and analogues thereof, beta-lapachone andanalogues thereof, biological vitamin D and analogues thereof, and amixture of these therapeutic agents. In another embodiment, thetherapeutic agent is in combination with a second therapeutic agent,wherein the therapeutic agent is one of paclitaxel, rapamycin, andanalogues thereof, and wherein the second therapeutic agent is one ofbeta-lapachone, biological active vitamin D and their analogues. In oneembodiment, the therapeutic agent is not water soluble.

In one embodiment, the additive enhances penetration and absorption ofthe therapeutic agent in the blood vessel. In another embodiment, theadditive penetrates the blood vessel, and the therapeutic agent is notwater-soluble. In another embodiment, the additive has water and ethanolsolubility of at least 1 mg/ml, and the therapeutic agent is not watersoluble.

In one embodiment of the balloon catheter, the catheter furthercomprises an adherent layer between the exterior surface of the balloonand the coating layer. In another embodiment, the catheter furthercomprises a top layer overlying the coating layer, wherein the top layerreduces loss of the therapeutic agent during transit through a body tothe blood vessel. The top layer comprises an additive selected fromthose additives according to embodiments of the invention describedherein. The top layer will be slowly dissolved during transit through abody to the body lumen to the target site for therapeutic intervention.This top layer will reduce drug loss during transit and increase thedrug available to the tissue when the medical device of embodiments ofthe present invention is pressed into contact with luminal tissue. Inone embodiment, the additive in the top layer is less hydrophilic thanthe additive in the coating layer. In another embodiment, the catheterfurther comprises a dimethylsulfoxide solvent layer, wherein thedimethylsulfoxide solvent layer is overlying the surface of the coatinglayer.

In one embodiment, the balloon catheter is capable of delivering thetherapeutic agent to the blood vessel in about 0.1 to 2 minutes. Inanother embodiment, the balloon catheter is capable of delivering thetherapeutic agent to the blood vessel in about 0.1 to 1 minute.

In one embodiment of the balloon catheter, the concentration of thetherapeutic agent in the coating layer is from 1 to 20 μg/mm². Inanother embodiment, the concentration of the therapeutic agent in thecoating layer is from 2 to 6 μg/mm². In one embodiment, theconcentration of the additive in the coating layer is from 1 to 10μg/mm². In one embodiment, the concentration of the contrast agent inthe coating layer is from 1 to 10 μg/mm².

In one embodiment, the present invention relates to a balloon catheterfor delivering a therapeutic agent to a blood vessel, the cathetercomprising a coating layer overlying the exterior surface of a balloon,the coating layer comprising a therapeutic agent, a contrast agent, andan additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the drug affinity part is at least one of ahydrophobic part, a part that has an affinity to the therapeutic agentby hydrogen bonding, and a part that has an affinity to the therapeuticagent by van der Waals interactions, wherein the additive is chosen fromp-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween 40, Tween60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryl oleate,PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In yet a further embodiment, the present invention relates to a ballooncatheter for delivering a therapeutic agent to a blood vessel. In oneaspect of this embodiment, the catheter comprises an elongate memberhaving a lumen and a distal end, an expandable balloon attached to thedistal end of the elongate member and in fluid communication with thelumen, and a coating layer overlying an exterior surface of the balloon.In one aspect of this embodiment, the coating layer overlying thesurface of the balloon comprises a lipophilic or water-insolubletherapeutic agent, a contrast agent, and an additive, wherein theadditive comprises a hydrophilic part and a drug affinity part, whereinthe drug affinity part comprises a hydrophobic part and/or has anaffinity to the therapeutic agent by hydrogen bonding and/or van derWaals interactions, wherein the additive is water-soluble, and whereinthe catheter is capable of delivering the therapeutic agent to the bloodvessel in less than about 2 minutes. In one aspect of this embodiment,the layer does not include a purely hydrophobic additive.

In one embodiment, the coating layer overlying the surface of theballoon consists essentially of the therapeutic agent, the contrastagent, and the additive. In one embodiment, the therapeutic agent in thecoating layer overlying the surface of the balloon is paclitaxel andanalogues thereof. In another embodiment, the therapeutic agent in thecoating layer overlying the surface of the balloon is rapamycin andanalogues thereof. In one embodiment, the coating layer overlying thesuface of the contains two therapeutic agents, one of which ispaclitaxel or analogues thereof or rapamycin or analogues thereof, andthe second of which is selected from agents that inhibit vasospasm.

In one embodiment, the concentration of the therapeutic agent in thecoating layer is from 2.5 to 6 μg/mm².

In one embodiment, the additive in the coating layer overlying thesurface of the balloon is an ionic or non-ionic surfactant. In anotherembodiment, the additive in the coating layer overlying the surface ofthe balloon is a vitamin or derivative thereof.

In one embodiment, the additive in the coating layer overlying thesurface of the balloon is chosen from Tyloxapol, Octoxynol, oleth,laureth, PEG-glyceryl, monolaurate, PEG-20 monolaurate, PEG 20monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide. In another embodiment, the additive in thecoating layer overlying the surface of the balloon is chosen from PEGfatty esters, PEG omega-3 fatty esters and alcohols, glycerol fattyesters, sorbitan fatty esters, PEG glyceryl fatty esters, PEG sorbitanfatty esters, sugar fatty esters, PEG sugar esters, vitamins andderivatives.

In another embodiment, the additive in the coating layer overlying thesurface of the balloon is chosen from p-isononylphenoxypolyglycidol, PEGlaurate, PEG oleate, PEG stearate, PEG glyceryl laurate, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate, Tween20, Tween 40, Tween 60, Tween 80, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-β-D-thioglucopyranoside. In yet another embodiment, the additivein the coating layer overlying the surface of the balloon is chosen frombenzalkonium chloride, benzethonium chloride, docecyl trimethyl ammoniumbromide, sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride,and dialkylesters of sodium sulfonsuccinic acid.

In one embodiment, the balloon catheter further comprises adimethylsulfoxide solvent layer overlying the coating layer, wherein thedimethylsulfoxide layer enhances the ability of the therapeutic agent topenetrate into the blood vessel. In another embodiment, the ballooncatheter further comprises an adherent layer between the exteriorsurface of the balloon and the coating layer. In yet another embodiment,the balloon catheter further comprises a top layer overlying the coatinglayer, wherein the top layer reduces loss of the therapeutic agentand/or contrast agent, and/or additive in the coating layer duringtransit through a body or blood vessel to the target site forintervention.

In yet a further embodiment, the present invention relates to apharmaceutical composition comprising a therapeutic agent, a contrastagent, and an additive, wherein the additive comprises a hydrophilicpart and a drug affinity part, wherein the drug affinity part is atleast one of a hydrophobic part, a part that has an affinity to thetherapeutic agent by hydrogen bonding, and a part that has an affinityto the therapeutic agent by van der Waals interactions, wherein theadditive is water-soluble, wherein the additive is at least one of asurfactant and a chemical compound.

In one embodiment, the contrast agent is chosen from iobitridol,iohexyl, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan,iotrolan, iodixanol, ioxaglate, and their derivatives. In oneembodiment, the surfactant is chosen from ionic, nonionic, aliphatic,and aromatic surfactants, PEG fatty esters, PEG omega-3 fatty esters,ether, and alcohols, glycerol fatty esters, sorbitan fatty esters, PEGglyceryl fatty esters, PEG sorbitan fatty esters, sugar fatty esters,PEG sugar esters and derivatives thereof. In one embodiment, thechemical compound has one or more hydroxyl, amino, carbonyl, carboxyl,acid, amide or ester groups. In one aspect of this embodiment, thechemical compound having one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester groups is chosen from amino alcohols,hydroxyl carboxylic acid, ester, and anhydrides, hydroxyl ketone,hydroxyl lactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyloxide, ethyl glycols, amino acids, peptides, proteins, sorbitan,glycerol, polyalcohol, phosphates, sulfates, organic acids, esters,salts, vitamins, combinations of amino alcohol and organic acid, andtheir substituted molecules.

In one embodiment of the pharmaceutical composition, the additive ischosen from p-isononylphenoxypolyglycidol, PEG laurate, Tween 20, Tween40, Tween 60, PEG oleate, PEG stearate, PEG glyceryl laurate, PEGglyceryl oleate, PEG glyceryl stearate, polyglyceryl laurate,plyglyceryl oleate, polyglyceryl myristate, polyglyceryl palmitate,polyglyceryl-6 laurate, plyglyceryl-6 oleate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, polyglyceryl-10 laurate, plyglyceryl-10oleate, polyglyceryl-10 myristate, polyglyceryl-10 palmitate PEGsorbitan monolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate,PEG sorbitan stearate, PEG oleyl ether, PEG laurayl ether, octoxynol,monoxynol, tyloxapol, sucrose monopalmitate, sucrose monolaurate,decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside; cystine,tyrosine, tryptophan, leucine, isoleucine, phenylalanine, asparagine,aspartic acid, glutamic acid, and methionine; acetic anhydride, benzoicanhydride, ascorbic acid, 2-pyrrolidone-5-carboxylic acid, sodiumpyrrolidone carboxylate, ethylenediaminetetraacetic dianhydride, maleicand anhydride, succinic anhydride, diglycolic anhydride, glutaricanhydride, acetiamine, benfotiamine, pantothenic acid; cetotiamine;cyclothiamine, dexpanthenol, niacinamide, nicotinic acid, pyridoxal5-phosphate, nicotinamide ascorbate, riboflavin, riboflavin phosphate,thiamine, folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU; albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,xylitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, retinoic acid, lysine acetate, gentisic acid, catechin,catechin gallate, tiletamine, ketamine, propofol, lactic acids, aceticacid, salts of any organic acid and organic amine, polyglycidol,glycerol, multiglycerols, galactitol, di(ethylene glycol), tri(ethyleneglycol), tetra(ethylene glycol), penta(ethylene glycol), poly(ethyleneglycol) oligomers, di(propylene glycol), tri(propylene glycol),tetra(propylene glycol, and penta(propylene glycol), poly(propyleneglycol) oligomers, a block copolymer of polyethylene glycol andpolypropylene glycol, and derivatives and combinations thereof.

In yet a further embodiment, the present invention relates to apharmaceutical composition for treating a diseased body lumen or cavityafter a surgical or interventional procedure, wherein the compositioncomprises a therapeutic agent, a contrast agent, and an additive,wherein the additive comprises a hydrophilic part and a drug affinitypart, wherein the therapeutic agent is not enclosed in micelles orliposomes or encapsulated in polymer particles.

In yet a further embodiment, the present invention relates to a methodfor treating a diseased body lumen or cavity after a surgical orinterventional procedure comprising delivering a pharmaceuticalcomposition at a surgical site by injection or spraying with a catheter,wherein the composition comprises a therapeutic agent, a contrast agent,and an additive, wherein the additive comprises a hydrophilic part and adrug affinity part, wherein the therapeutic agent is not enclosed inmicelles or liposomes or encapsulated in polymer particles.

In yet a further embodiment, the present invention relates to apharmaceutical composition for treating a cancer including cancers ofthe ovary, breast, lung, esophagus, head and neck region, bladder,brain, liver, colon and lymphomas, wherein the composition comprises atherapeutic agent, a contrast agent, and an additive, wherein theadditive comprises a hydrophilic part and a drug affinity part, whereinthe drug affinity part is a hydrophobic part and/or has an affinity tothe therapeutic agent by hydrogen bonding and/or van der Waalsinteractions, and wherein the therapeutic agent is not enclosed inmicelles or liposomes or encapsulated in polymer particles. In oneaspect of this embodiment, the therapeutic agent is chosen frompaclitaxel and analogues thereof and rapamycin and analogues thereof.

In yet a further embodiment, the present invention relates to a solutionfor coating a medical device. In one aspect of this embodiment, thesolution comprises an organic solvent, a therapeutic agent, a contrastagent, and an additive, wherein the additive comprises a hydrophilicpart and a drug affinity part, wherein the drug affinity part is ahydrophobic part and/or has an affinity to the therapeutic agent byhydrogen bonding and/or van der Waals interactions, and wherein thetherapeutic agent is not enclosed in micelles liposomes or encapsulatedin polymer particles. In one aspect of this embodiment, the solutiondoes not include a purely hydrophobic additive. In another embodiment,the solution for coating a medical device does not include oil, a lipid,or a polymer.

In one embodiment, the additive in the coating solution is an ionic ornon-ionic surfactant. In another embodiment, the additive is a vitaminor derivative thereof.

In one embodiment, the additive in the coating solution is chosen fromTyloxapol, Octoxynol, oleth, laureth, PEG-glyceryl, monolaurate, PEG-20monolaurate, PEG 20 monooleate, PEG 20 glyceryl monooleate, Nonoxynol,Nonylphenylpoly(glycidol), Octyl-betha-D-glycopyranoside, anddeconoyl-N-methylglucamide.

In another embodiment, the additive in the coating solution is chosenfrom PEG fatty esters, PEG omega-3 fatty esters and alcohols, glycerolfatty esters, sorbitan fatty esters, PEG glyceryl fatty esters, PEGsorbitan fatty esters, sugar fatty esters, PEG sugar esters, vitaminsand derivatives, amino acids, multi amino acids and derivatives,peptides, polypeptides, proteins, quaternary ammonium salts, organicacids, salts and anhydrides.

In another embodiment, the additive in the coating solution is chosenfrom p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEGstearate, PEG glyceryl laurate, PEG glyceryl oleate, PEG glycerylstearate, polyglyceryl laurate, plyglyceryl oleate, polyglycerylmyristate, polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6oleate, polyglyceryl-6 myristate, polyglyceryl-6 palmitate,polyglyceryl-10 laurate, plyglyceryl-10 oleate, polyglyceryl-10myristate, polyglyceryl-10 palmitate PEG sorbitan monolaurate, PEGsorbitan monolaurate, PEG sorbitan monooleate, PEG sorbitan stearate,PEG oleyl ether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol,Tween 20, Tween 40, Tween 60, Tween 80, sucrose monopalmitate, sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside, benzalkoniumchloride, benzethonium chloride, docecyl trimethyl ammonium bromide,sodium docecylsulfates, dialkyl methylbenzyl ammonium chloride, anddialkylesters of sodium sulfonsuccinic acid (ionic surfactants).

In another embodiment, the additive in the solution is chosen fromsorbitan fatty esters. In yet another embodiment, the additive in thecoating solution is chosen from benzalkonium chloride, benzethoniumchloride, docecyl trimethyl ammonium bromide, sodium docecylsulfates,dialkyl methylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid.

In one embodiment, the therapeutic agent in the coating solution ispaclitaxel or analogues thereof or rapamycin or analogues thereof.

In one embodiment, the content of the therapeutic agent in the solutionis from 0.5-50% by weight. In one embodiment, the content of theadditive in the coating solution is from 1-45% by weight. In oneembodiment, the content of the contrast agent in the coating solution isfrom 1-45% by weight.

In one embodiment, the additive in the solution is soluble in aqueoussolvent and is soluble in organic solvent.

In yet a further embodiment, the present invention relates to a medicaldevice for delivering a therapeutic agent to a tissue, the devicecomprising a first layer applied to an exterior surface of the medicaldevice, and a second layer overlying the first layer. In one aspect ofthis embodiment, the first layer comprises a therapeutic agent, and thesecond layer comprises a contrast agent and an additive, wherein theadditive comprises a hydrophilic part and a drug affinity part, andwherein the therapeutic agent in the first layer is not enclosed inmicelles or liposomes or encapsulated in polymer particles. In oneaspect of this embodiment, the first layer further comprises a contrastagent and an additive. In another aspect of this embodiment, the secondlayer further comprises a therapeutic agent. In yet a further aspect ofthis embodiment, the first layer further comprises an additive and thesecond layer further comprises a therapeutic agent.

In a further embodiment, the present invention relates to a two layercoating comprising a first layer comprising a therapeutic agent, and asecond layer comprising a contrast agent and an additive. In one aspectof this embodiment, the second layer may be overlying the first layer.In one aspect of this embodiment, the additive in the second layercomprises a hydrophilic part and a drug affinity part, and thetherapeutic agent in the first layer is not enclosed in micelles orliposomes or encapsulated in polymer particles. In one aspect of thisembodiment, the first layer further comprises an additive. In anotheraspect of this embodiment, the second layer further comprises atherapeutic agent. In yet another aspect of this embodiment, the firstlayer further comprises an additive or a contrast agent and the secondlayer further comprises a therapeutic agent.

In a further embodiment, the present invention relates to a method forpreparing a medical device. In one aspect of this embodiment, the methodcomprises (a) preparing a coating solution comprising an organicsolvent, a therapeutic agent, a contrast agent, and an additive, whereinthe additive comprises a hydrophilic part and a drug affinity part,wherein the drug affinity part is a hydrophobic part and/or has anaffinity to the therapeutic agent by hydrogen bonding and/or van derWaals interactions, and wherein the therapeutic agent is not enclosed inmicelles or encapsulated in polymer particles, (b) applying the coatingsolution to a medical device, and (c) drying the coating solution,forming a coating layer. In one aspect of this embodiment, the coatingis applied by dipping a portion of the exterior surface of the medicaldevice in the coating solution. In another aspect of this embodiment,the coating is applied by spraying a portion of the exterior surface ofthe medical device with a coating solution. In another aspect of thisembodiment, steps (b) and (c) are repeated until a therapeuticallyeffective amount of the therapeutic agent in the coating layer isdeposited on the surface of the medical device. In another aspect ofthis embodiment, the total thickness of the coating layer is from about0.1 to 200 microns. In another aspect of this embodiment, theconcentration density of the at least one therapeutic agent applied tothe surface of the medical device is from about 1 to 20 μg/mm², or inanother aspect from about 2 to 6 μg/mm². In yet another aspect of thisembodiment, the method further comprises applying a dimethylsulfoxidesolvent to the dried coating layer obtained in step (c).

In another embodiment, the method for preparing the medical devicecomprises, (a) preparing a coating solution comprising an organicsolvent, a therapeutic agent, a contrast agent, and an additive, whereinthe additive is an anhydride, (b) applying the coating solution to amedical device, (c) drying the coating solution, forming a coatinglayer, and (d) hydrolyzing the anhydride to an acid group.

In a further embodiment, the present invention relates to a method forpreparing a drug coated balloon catheter. In one aspect of thisembodiment, the method comprises, (a) preparing a coating solutioncomprising an organic solvent, a therapeutic agent, a contrast agent,and an additive, (b) applying the coating solution to an inflatedballoon catheter, and (c) deflating and folding the balloon catheter anddrying the coating solution to increase uniformity of drug coating.

In a further embodiment, the present invention relates to a method fortreating a blood vessel. In one aspect of this embodiment, the methodcomprises inserting a medical device comprising a coating layer into theblood vessel, wherein the coating layer comprises a therapeutic agent, acontrast agent, and an additive, wherein the additive comprises ahydrophilic part and a drug affinity part, and wherein the therapeuticagent is not enclosed in micelles or liposomes or encapsulated inpolymer particles, and releasing the therapeutic agent into the tissueof the blood vessel in 2 minutes or less.

In a further embodiment, the present invention relates to a method fortreating a total occlusion or narrowing of body passages. In one aspectof this embodiment, the method comprises removing plaques in the bodypassages by one of a debulking catheter, a laser atherectomy, adirecting atherectomy, or a rotational atherectomy, inserting a medicaldevice comprising a coating layer into the body passages, wherein thecoating layer comprises a therapeutic agent, a contrast agent, and anadditive, wherein the additive comprises a hydrophilic part and a drugaffinity part, and releasing the therapeutic agent, the contrast agent,and the additive, and delivering the therapeutic agent into the tissueof the body passage or lumen, such as a blood vessel, in 2 minutes orless.

In a further embodiment, the present invention relates to a method fortreating tissue of a body comprising bringing a medical devicecomprising a coating layer into contact with tissue of the body, whereinthe coating layer comprises a therapeutic agent, a contrast agent, andan additive, wherein the additive comprises a hydrophilic part and adrug affinity part, and releasing the therapeutic agent, the contrastagent, and the additive, and delivering the therapeutic agent into thetissue in 2 minutes or less. In one aspect of this embodiment, thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages.

In yet a further embodiment, the present invention relates to a processof producing a balloon catheter. In one aspect of this embodiment, theprocess comprises preparing a solution comprising an organic solvent, atherapeutic agent, a contrast agent, and an additive, wherein theadditive comprises a hydrophilic part and a drug affinity part, andwherein the therapeutic agent is not enclosed in micelles or liposomesor encapsulated in polymer particles, applying the solution to theballoon catheter, and evaporating the solvent.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, a contrast agent, andan additive, wherein the additive is one of PEG fatty ester, PEG fattyether, and PEG fatty alcohols. In one aspect of this embodiment, theadditive is chosen from PEG-8 laurate, PEG-8 oleate, PEG-8 stearate,PEG-9 oleate, PEG-10 laurate, PEG-10 oleate, PEG-12 laurate, PEG-12oleate, PEG-15 oleate, PEG-20 laurate, PEG-20 oleate, PEG-20 dilaurate,PEG-20 dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32dioleate. In another aspect of this embodiment, the tissue includestissue of one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages. In yet another aspect ofthis embodiment, the device includes one of a balloon catheter, aperfusion balloon catheter, an infusion catheter, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, a contrast agent, andan additive, wherein the additive is one of glycerol and polyglycerolfatty esters and PEG glycerol fatty esters. In one aspect of thisembodiment, the additive is chosen from polyglyceryl oleate,polyglyceryl-2 dioleate, polyglyceryl-10 trioleate, polyglycerylstearate, polyglyceryl laurate, polyglyceryl myristate, polyglycerylpalmitate, polyglyceryl linoleate, polyglyceryl-10 laurate,polyglyceryl-10 oleate, polyglyceryl-10 mono, dioleate, polyglyceryl-10stearate, polyglyceryl-10 laurate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, polyglyceryl-10 linoleate, polyglyceryl-6stearate, polyglyceryl-6 laurate, polyglyceryl-6 myristate,polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate, polyglycerylpolyricinoleates, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, and PEG-30 glyceryloleate. In another aspect of this embodiment, the tissue includes tissueof one of coronary vasculature, peripheral vasculature, cerebralvasculature, esophagus, airways, sinus, trachea, colon, biliary tract,urinary tract, prostate, and brain passages. In yet another aspect ofthis embodiment, the device includes one of a balloon catheter, aperfusion balloon catheter, an infusion catheter, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, a contrast agent, andan additive, wherein the additive is one of sorbitan fatty esters, andPEG sorbitan esters. In one aspect of this embodiment, the additive ischosen from sorbitan monolaurate, sorbitan monopalmitate, sorbitanmonooleate, sorbitan monostearate, Tween 20, Tween 40, Tween 60, Tween80, PEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20sorbitan monooleate, and PEG-20 sorbitan monostearate. In another aspectof this embodiment, the tissue includes tissue of one of coronaryvasculature, peripheral vasculature, cerebral vasculature, esophagus,airways, sinus, trachea, colon, biliary tract, urinary tract, prostate,and brain passages. In yet another aspect of this embodiment, the deviceincludes one of a balloon catheter, a perfusion balloon catheter, aninfusion catheter, perforated balloon, porous balloon, weeping balloon,a cutting balloon catheter, a scoring balloon catheter, a lasercatheter, an atherectomy device, a debulking catheter, a stent, afilter, a stent graft, a covered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, a contrast agent, andan additive, wherein the additive is a chemical compound containing aphenol moiety. In one aspect of this embodiment, the additive is chosenfrom p-isononylphenoxypolyglycidol, octoxynol, monoxynol, tyloxapol,octoxynol-9, and monoxynol-9. In another aspect of this embodiment, thetissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, an infusion catheter,perforated balloon, porous balloon, weeping balloon, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, a contrast agent, andan additive, wherein the additive is a sugar or sugar derivative. In oneaspect of this embodiment, the additive is chosen from sucrosemonolaurate, decanoyl-N-methylglucamide, n-decyl-β-D-glucopyranoside,n-decyl-β-D-maltopyranoside, n-dodecyl-β-D-glucopyranoside,n-dodecyl-β-D-maltoside, heptanoyl-N-methylglucamide,n-heptyl-β-D-glucopyranoside, n-heptyl-β-D-thioglucoside,n-hexyl-β-D-glucopyranoside, nonanoyl-N-methylglucamide,n-noyl-β-D-glucopyranoside, octanoyl-N-methylglucamide,n-octyl-β-D-glucopyranoside, octyl-β-D-thioglucopyranoside,D-glucoascorbic acid and its salt, triethanolamine, diethanolamine,meglumine, tromethamine, glucamine, glucosamine, glucoheptonic acid,glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid,vanillin, vanillic acid, vanillic acid diethylamide, lysine acetatesalt, gentisic acid, lactobionic acid, lactitol, diethylene glycol,triethylene glycol, tetraethylene glycol, xylitol, 2-ethoxyethanol,sugars, galactose, glucose, mannose, xylose, sucrose, lactose, maltose,sorbitol, cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen,ibuprofen, catechin, catechin gallate, methyl paraben, ethyl paraben,propyl paraben, butyl paraben, tiletamine, ketamine, propofol, lacticacids, acetic acid, salts of any organic acid and amine described above.In another aspect of this embodiment, the tissue includes tissue of oneof coronary vasculature, peripheral vasculature, cerebral vasculature,esophagus, airways, sinus, trachea, colon, biliary tract, urinary tract,prostate, and brain passages. In yet another aspect of this embodiment,the device includes one of a balloon catheter, a perfusion ballooncatheter, an infusion catheter, a cutting balloon catheter, a scoringballoon catheter, a laser catheter, an atherectomy device, a debulkingcatheter, a stent, a filter, a stent graft, a covered stent, a patch, awire, and a valve.

In yet a further embodiment, the present invention relates to a medicaldevice comprising a layer overlying an exterior surface of the medicaldevice, the layer comprising a therapeutic agent, a contrast agent, andan additive, wherein the additive is an ionic surfactant. In one aspectof this embodiment, the additive is chosen from benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, docecyl trimethylammonium bromide, sodium docecylsulfates, dialkyl methylbenzyl ammoniumchloride, edrophonium chloride, domiphen bromide, and dialkylesters ofsodium sulfonsuccinic acid, sodium dioctyl sulfosuccinate, sodiumcholate, and sodium taurocholate. In another aspect of this embodiment,the tissue includes tissue of one of coronary vasculature, peripheralvasculature, cerebral vasculature, esophagus, airways, sinus, trachea,colon, biliary tract, urinary tract, prostate, and brain passages. Inyet another aspect of this embodiment, the device includes one of aballoon catheter, a perfusion balloon catheter, an infusion catheter,perforated balloon, porous balloon, weeping balloon, a cutting ballooncatheter, a scoring balloon catheter, a laser catheter, an atherectomydevice, a debulking catheter, a stent, a filter, a stent graft, acovered stent, a patch, a wire, and a valve.

Many embodiments of the present invention are particularly useful fortreating vascular disease and for reducing stenosis and late luminalloss, or are useful in the manufacture of devices for that purpose.

It is understood that both the foregoing general description and thefollowing detailed description are exemplary and explanatory only andare not restrictive of the present invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of an exemplary embodiment of a ballooncatheter according to the present invention.

FIGS. 2A-2C are cross-sectional views of different embodiments of thedistal portion of the balloon catheter of FIG. 1, taken along line A-A,showing exemplary coating layers.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Embodiments of the present invention relate to medical devices,including particularly balloon catheters and stents, having a rapiddrug-releasing coating and methods for preparing such coated devices.The therapeutic agent according to embodiments of the present inventiondoes not require a delayed or long term release and instead preferablyis released in a very short time period, from seconds to minutes, toprovide a therapeutic effect upon contact with tissue. An object ofembodiments of the present invention is to facilitate rapid andefficient uptake of drug by target tissue during transitory devicedeployment at a target site.

As shown in FIG. 1, in one embodiment, the medical device is a ballooncatheter. The balloon catheter may be any suitable catheter for thedesired use, including conventional balloon catheters known to one ofordinary skill in the art. For example, balloon catheter 10 may includean expandable, inflatable balloon 12 at a distal end of the catheter 10,a handle assembly 16 at a proximal end of the catheter 10, and anelongate flexible member 14 extending between the proximal and distalends. Handle assembly 16 may connect to and/or receive one or moresuitable medical devices, such as a source of inflation media (e.g.,air, saline, or contrast media). Flexible member 14 may be a tube madeof suitable biocompatible material and having one or more lumenstherein. At least one of the lumens is configured to receive inflationmedia and pass such media to balloon 12 for its expansion. The ballooncatheter may be a rapid exchange or over-the-wire catheter and made ofany suitable biocompatible material.

In one embodiment, the present invention provides a medical device fordelivering a therapeutic agent to a tissue. The device includes a layerapplied to an exterior surface of the medical device, such as a ballooncatheter or stent, for example. The layer includes a therapeutic agent,a contrast agent, and an additive. For example, as shown in theembodiment depicted in FIG. 2A, the balloon 12 is coated with a layer 20that includes a therapeutic agent, a contrast agent, and an additive. Insome embodiments, the layer consists essentially of a therapeutic agent,a contrast agent, and an additive, i.e., the layer includes only thetherapeutic agent, the contrast agent, and the additive, without anyother materially significant components. In some embodiments, the devicemay optionally include an adherent layer. For example, as shown in theembodiment depicted in FIG. 2B, the balloon 12 is coated with anadherent layer 22. A layer 24 that includes a therapeutic agent, acontrast agent, and an additive is overlying the adherent layer. Theadherent layer, which is a separate layer underlying the drug coatinglayer, improves the adherence of the drug coating layer to the exteriorsurface of the medical device and protects coating integrity. Forexample, if the therapeutic agent, contrast agent, and additive differin their adherence to the medical device, the adherent layer may preventdifferential loss of components and maintain drug-to-additive ratio anddrug-to-contrast agent ratio in the coating during transit to a targetsite for therapeutic intervention. Furthermore, the adherent layer mayfunction to facilitate rapid release of coating layer components off thedevice surface upon contact with tissues at the target site. In otherembodiments, the device may include a top layer. The top layer mayprevent loss of the drug layer before it is brought into contact withtarget tissues, for example during transit of the balloon 12 to the siteof therapeutic intervention or during the first moments of inflation ofballoon 12 before coating layer 20 is pressed into direct contact withtarget tissue. In one embodiment, the therapeutic agent in the coatinglayer is lipophilic or water-insoluble.

In embodiments of the coatings for medical devices of the presentinvention, the lipophilic or water-insoluble therapeutic agent isinterdispersed in the matrix or dispersion of the contrast agent and theadditive in the coating layer overlying the medical device.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Inone embodiment, the ratio by weight of the therapeutic agent to thecontrast agent in the layer is from about 0.05 to 100, for example, fromabout 0.1 to 5, from 0.5 to 3, and further for example, from about 0.8to 1.2. In one embodiment, the ratio by weight of the drug to theadditive in the layer is from about 0.05 to 100, for example, from about0.1 to 5, from 0.5 to 2, and further for example, from about 0.8 to 1.2

In other embodiments, the layer may include a therapeutic agent, acontrast agent, and more than one additive. For example, one additivemay serve to improve balloon adhesion of the contrast agent or ofanother additive that is superior at promoting tissue uptake of drug.Alternatively, one additive may decrease balloon adhesion of anotheradditive, in order to accelerate elution of the therapeutic agent offthe surface of the device during brief deployment at the target site.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise a contrast agent and an additiveor additives. The second layer comprises a contrast agent and anadditive or additives. The second layer may optionally include at leasta therapeutic agent. When the first and second layers both contain atherapeutic agent, the content of the therapeutic agent in the secondlayer is lower than the content of the therapeutic agent in the firstlayer. In one embodiment, the second layer is overlying the first layer.In this arrangement, the second layer can prevent drug loss duringdeployment of the medical device into body passageways, for example, asa balloon catheter traverses the tortuous anatomy to a tissue site inthe vasculature.

In another embodiment, the device comprises two layers applied to anexterior surface of the medical device, and particularly a ballooncatheter, for example. The first layer comprises a therapeutic agent.The first layer may optionally comprise a contrast agent and an additiveor additives. The second layer comprises a contrast agent and anadditive or additives. The second layer may optionally include at leasta therapeutic agent. When the first and second layers both contain atherapeutic agent, the content of the therapeutic agent in the firstlayer is lower than the content of the therapeutic agent in the secondlayer. In one embodiment, the second layer is overlying the first layer.This arrangement is useful, for example, in the case of a therapeuticagent that adheres too tightly to the balloon surface to rapidly eluteoff the balloon when inflated at the target site. In this arrangement,the first layer functions to facilitate rapid release of the bulk ofdrug, which is in the second layer, off the surface of the device whileit is inflated at the target site of therapeutic intervention.

In other embodiments, two or more therapeutic agents are used incombination in the drug-additive and contrast agent layer.

In a further embodiment, the device having a two layer coating mayoptionally include an adherent layer. The adherent layer does notcontain a therapeutic agent. For example, as shown in the embodimentdepicted in FIG. 2C, the balloon 12 is coated with an adherent layer 22.A first layer 26 that comprises a therapeutic agent and optionally acontrast agent and an additive or additives is overlying the adherentlayer 22. A second layer 28 that comprises a contrast agent and anadditive and optionally a therapeutic agent is overlying the first layer26. The adherent layer improves the adherence of the first layer to theexterior surface of the medical device and protects the integrity of thefirst layer. For example, if drug, contrast agent, and additive oradditives in the first layer differ in their strength of adherence tothe medical device, the adherent layer may prevent differential loss ofcomponents and maintain drug-to-additive, drug-to-contrast agent ratio,contrast agent-to-additive ratio, and additive-to-additive ratio in thefirst and second layers during transit to a target site for therapeuticintervention. Furthermore, the adherent layer may function to facilitaterapid elution of coating layer off the device surface upon contact withtissues at the target site. In one embodiment, the first layer, thesecond layer, and the adherent layer each contain an additive orcontrast agent.

Optionally, post-treatment with dimethylsulfoxide (DMSO) or othersolvent may be advantageous since DMSO may further enhance penetrationand absorption of drug into tissue. DMSO displaces water from the lipidhead groups and protein domains of the membrane lipid bilayer of targetcells to indirectly loosen the lipid structure, accelerating drugabsorption and penetration.

In a further embodiment, the present invention relates to apharmaceutical composition for treating a diseased body lumen orcavities after surgical or interventional procedures (PTCA, PTA, stentplacement, excision of diseased tissue such as cancer, and relieving ortreating stenosis), wherein the pharmaceutical composition comprises atherapeutic agent, a contrast agent, and an additive, wherein theadditive comprises a hydrophilic part and a drug affinity part, whereinthe drug affinity part is a hydrophobic part and/or has an affinity tothe therapeutic agent by hydrogen bonding and/or van der Waalsinteractions, and wherein the therapeutic agent is not enclosed inmicelles or liposomes or encapsulated in polymer particles.

In another embodiment, a method of preventing complications orrecurrence of disease (such as cancer or restenosis) after a surgical orinterventional procedure such as PTCA, PTA, stent deployment, stenosisor plaque removal by debulking, atherectomy, or laser procedures, thepharmaceutical composition is locally delivered at or near the site ofintervention by means of a coated medical device (such as a drug-coatedballoon), or by spray, by injection, or by deposition. For example, thepharmaceutical composition may be delivered by spray, injection, balloonor other method of deposition, into cavities created by surgical removalof cancer tissue in order to reduce the risk of recurrence. As anotherexample, a method for delivering the pharmaceutical compositioncomprises inserting a medical device (such as guide catheter or a druginfusion catheter) into the blood to inject the pharmaceuticalcomposition after a vascular intervention such as PTCA, PTA, or stentplacement to prevent restenosis, wherein the pharmaceutical compositioncomprises a therapeutic agent, a contrast agent, and an additive,wherein the additive comprises a hydrophilic part and a drug affinitypart, wherein the drug affinity part is a hydrophobic part and/or has anaffinity to the therapeutic agent by hydrogen bonding and/or Van derWaals interactions, and wherein the therapeutic agent is not enclosed inmicelles or liposomes or encapsulated in polymer particles.

Many embodiments of the present invention are particularly useful fortreating vascular disease and for reducing stenosis and late luminalloss, or are useful in the manufacture of devices for that purpose.

Contrast Agent

X-ray contrast agents for intravascular injection are based upon thetriiodobenzene ring substituted with two or three additional hydrophilicgroups. In the case of biliary contrast agents (compounds that are takenup by the liver and excreted mainly by the biliary tract), twohydrophilic groups are introduced. For angiographic/urographic agents(compounds that stay within the extravascular distribution volume andare excreted by the kidneys), three hydrophilic groups are introduced.The monomers are exclusively derived from aminoisophathalic acid. Theyonly differ by their side-chains, which determine their physiochemicalcharacteristics such as solubility, hydrophilicity, viscosity, andosmolality. Many of these agents contain covalently-bonded iodine. Theaqueous solubility of X-ray contrast agents is generally extremely highbeing in the order of 1000 mg/ml. Most preparations of X-ray contrastagents are over-saturated solutions.

The contrast agent in embodiments of the present invention includesiobitridol, iohexyl, iomeprol, iopamidol, iopentol, iopromide, ioversol,ioxilan, iotrolan, iodixanol, ioxaglate, and their derivatives. Theseare provided by way of example, and there are many other contrast agentsknown in the art that are useful in embodiments of the presentinvention.

Additive

The additive of embodiments of the present invention has two parts. Onepart is hydrophilic and the other part is a drug affinity part. The drugaffinity part is a hydrophobic part and/or has affinity to thetherapeutic agent by hydrogen bonding and/or charge and/or van der Waalsinteractions. The drug affinity part of the additive may bind thelipophilic drug, such as rapamycin or paclitaxel. In embodiments of thepresent invention, the additive is interdispersed with the lipophilic orwater-insoluble drug and the contrast agent in the coating of a medicaldevice. By nature of its two parts, the additives of embodiments of thepresent invention have affinity to both the hydrophilic contrast agentand to the lipophilic or water-insoluble therapeutic agent. The additiveimproves the compatability of the therapeutic agent and the contrastagent in the coating solution and coating layer. The additive improvesthe physical properties of the coating, its ability to resist flaking orphysical disruption, and it improves and preserves coating integrity anduniformity and consistency of drug distribution in the coating.

The hydrophilic portion may also function to accelerate diffusion andincrease permeation of the drug into tissue. It may facilitate rapidmovement of drug off the medical device during deployment at the targetsite by preventing hydrophobic drug molecules from clumping to eachother and to the surface of the device, increasing drug solubility ininterstitial spaces, and/or accelerating drug passage through polar headgroups to the lipid bilayer of cell membranes of target tissues.

The additives of embodiments of the present invention have two partsthat function together to improve the compatability of contrast agentwith the therapeutic agent in the coating and to improve the physicalproperties of the coating. Since one part of the additive has affinityto contrast agent and the other part has affinity to lipophilic orwater-insoluble drug, the additives of embodiments of the presentinvention improve the compatability of these agents in the coatinglayer. The additives thereby improve the coating layer's resistance tophysical disruption and the uniformity and consistency of drugdistribution in and integrity of the coating. The additives ofembodiments of the present invention may also facilitate rapid releaseof drug off the device surface and uptake by target tissue duringdeployment (by accelerating drug contact with tissues for which drug hashigh affinity) while preventing the premature release of drug from thedevice surface prior to device deployment at the target site.

In embodiments of the present invention, the therapeutic agent, thecontrast agent, and additive are rapidly released after the medicaldevice is brought into contact with tissue, and the therapeutic agent isreadily absorbed by tissue. For example, certain embodiments of devicesof the present invention include drug coated balloon catheters thatdeliver a lipophilic anti-proliferative pharmaceutical (such aspaclitaxel or rapamycin) to vascular tissue through brief, directpressure contact at high drug concentration during balloon angioplasty.The lipophilic drug is preferentially retained in target tissue at thedelivery site, where it inhibits hyperplasia and restenosis yet allowsendothelialization. In these embodiments, coating formulations of thepresent invention not only facilitate rapid release of drug from theballoon surface and transfer of drug into target tissues duringdeployment, but also prevent drug from diffusing away from the deviceduring transit through tortuous arterial anatomy prior to reaching thetarget site and from exploding off the device during the initial phaseof balloon inflation, before the drug coating is pressed into directcontact with the surface of the vessel wall.

The additive according to certain embodiments, has a drug affinity partand a hydrophilic part. The drug affinity part is a hydrophobic partand/or has an affinity to the therapeutic agent by hydrogen bondingand/or van der Waals interactions. The drug affinity part may includealiphatic and aromatic organic hydrocarbon compounds, such as benzene,toluene, and alkanes, among others. These parts are not water soluble.They may bind both hydrophobic drug, with which they share structuralsimilarities, and lipids of cell membranes. The drug affinity part mayinclude functional groups that can form hydrogen bonds with drug andwith itself. The hydrophilic part may include hydroxyl groups, aminegroups, amide groups, carbonyl groups, carboxylic acid and anhydrides,ethyl oxide, ethyl glycol, polyethylene glycol, ascorbic acid, aminoacid, amino alcohol, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic salts and their substituted molecules,among others. One or more hydroxyl, carboxyl, acid, amide or aminegroups, for example, may be advantageous since they easily displacewater molecules that are hydrogen-bound to polar head groups and surfaceproteins of cell membranes and may function to remove this barrierbetween hydrophobic drug and cell membrane lipid. These parts candissolve in water and polar solvents. These additives are not oils,lipids, or polymers. The therapeutic agent is not enclosed in micellesor liposomes or encapsulated in polymer particles. The additives ofembodiments of the present invention have components to both bind drugand contrast agent, improving the physical properties of the coating andfacilitating the rapid movement of drug off the surface of the medicaldevice during deployment and into target tissues.

The additives in embodiments of the present invention are surfactantsand chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties. The surfactants include ionic,nonionic, aliphatic, and aromatic surfactants. The chemical compoundswith one or more hydroxyl, amino, carbonyl, carboxyl, acid, amide orester moieties are chosen from amino alcohols, hydroxyl carboxylic acidand anhydrides, ethyl oxide, ethyl glycols, amino acids, peptides,proteins, sugars, glucose, sucrose, sorbitan, glycerol, polyalcohol,phosphates, sulfates, organic acids, esters, salts, vitamins, and theirsubstituted molecules.

As is well known in the art, the terms “hydrophilic” and “hydrophobic”are relative terms. To function as an additive in exemplary embodimentsof the present invention, the compound includes polar or chargedhydrophilic moieties and moieties with affinity to the therapeuticagent, such as nonpolar, hydrophobic or lipophilic moieties or moietiesthat form hydrogen bonds and/or van der Waals interactions with drug.

An empirical parameter commonly used in medicinal chemistry tocharacterize the relative hydrophilicity and hydrophobicity ofpharmaceutical compounds is the partition coefficient, P, the ratio ofconcentrations of unionized compound in the two phases of a mixture oftwo immiscible solvents, usually octanol and water, such thatP=([solute]octanol/[solute]water). Compounds with higher log Ps are morehydrophobic, while compounds with lower log Ps are more hydrophilic.Lipinski's rule suggests that pharmaceutical compounds having log P<5are typically more membrane permeable. For purposes of certainembodiments of the present invention, it is preferable that the additivehas log P less than log P of the drug to be formulated (as an example,log P of paclitaxel is 7.4). A greater log P difference between the drugand the additive can facilitate phase separation of drug. For example,if log P of the additive is much lower than log P of the drug, theadditive may accelerate the release of drug in an aqueous environmentfrom the surface of a device to which drug might otherwise tightlyadhere, thereby accelerating drug delivery to tissue during briefdeployment at the site of intervention. In certain embodiments of thepresent invention, log P of the additive is negative. In otherembodiments, log P of the additive is less than log P of the drug Whilea compound's octanol-water partition coefficient P or log P is useful asa measurement of relative hydrophilicity and hydrophobicity, it ismerely a rough guide that may be useful in defining suitable additivesfor use in embodiments of the present invention.

Suitable additives that can be used in embodiments of the presentinvention include, without limitation, organic and inorganicpharmaceutical excipients, natural products and derivatives thereof(such as sugars, vitamins, amino acids, peptides, proteins, and fattyacids), low molecular weight oligomers, surfactants (anionic, cationic,non-ionic, and ionic), and mixtures thereof. The following detailed listof additives useful in the present invention is provided for exemplarypurposes only and is not intended to be comprehensive. Many otheradditives may be useful for purposes of the present invention.

Surfactants

The surfactant can be any surfactant suitable for use in pharmaceuticalcompositions. Such surfactants can be anionic, cationic, zwitterionic ornon-ionic. Mixtures of surfactants are also within the scope of theinvention, as are combinations of surfactant and other additives.Surfactants often have one or more long aliphatic chains such as fattyacids that may insert directly into lipid bilayers of cell membranes toform part of the lipid structure, while other components of thesurfactants loosen the lipid structure and enhance drug penetration andabsorption.

An empirical parameter commonly used to characterize the relativehydrophilicity and hydrophobicity of surfactants is thehydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLBvalues are more hydrophobic, and have greater solubility in oils, whilesurfactants with higher HLB values are more hydrophilic, and havegreater solubility in aqueous solutions. Using HLB values as a roughguide, hydrophilic surfactants are generally considered to be thosecompounds having an HLB value greater than about 10, as well as anionic,cationic, or zwitterionic compounds for which the HLB scale is notgenerally applicable. Similarly, hydrophobic surfactants are compoundshaving an HLB value less than about 10. In certain embodiments of thepresent invention, a higher HLB value is preferred, since increasedhydrophilicity may facilitate release of hydrophobic drug from thesurface of the device. In one embodiment, the HLB of the surfactantadditive is higher than 10. In another embodiment, the additive HLB ishigher than 14. Alternatively, surfactants having lower HLB may bepreferred when used to prevent drug loss prior to device deployment atthe target site, for example in a top coat over a drug layer that has avery hydrophilic additive.

It should be understood that the HLB value of a surfactant is merely arough guide generally used to enable formulation of industrial,pharmaceutical and cosmetic emulsions, for example. For many importantsurfactants, including several polyethoxylated surfactants, it has beenreported that HLB values can differ by as much as about 8 HLB units,depending upon the empirical method chosen to determine the HLB value(Schott, J. Pharm. Sciences, 79(1), 87-88 (1990)). Keeping theseinherent difficulties in mind, and using HLB values as a guide,surfactants may be identified that have suitable hydrophilicity orhydrophobicity for use in embodiments of the present invention, asdescribed herein.

PEG-Fatty Acids and PEG-Fatty Acid Mono and Diesters

Although polyethylene glycol (PEG) itself does not function as asurfactant, a variety of PEG-fatty acid esters have useful surfactantproperties. Among the PEG-fatty acid monoesters, esters of lauric acid,oleic acid, and stearic acid are most useful in embodiments of thepresent invention. Preferred hydrophilic surfactants include PEG-8laurate, PEG-8 oleate, PEG-8 stearate, PEG-9 oleate, PEG-10 laurate,PEG-10 oleate, PEG-12 laurate, PEG-12 oleate, PEG-15 oleate, PEG-20laurate and PEG-20 oleate. The HLB values are in the range of 4-20.

Polyethylene glycol fatty acid diesters are also suitable for use assurfactants in the compositions of embodiments of the present invention.Most preferred hydrophilic surfactants include PEG-20 dilaurate, PEG-20dioleate, PEG-20 distearate, PEG-32 dilaurate and PEG-32 dioleate. TheHLB values are in the range of 5-15.

In general, mixtures of surfactants are also useful in embodiments ofthe present invention, including mixtures of two or more commercialsurfactants as well as mixtures of surfactants with another additive oradditives. Several PEG-fatty acid esters are marketed commercially asmixtures or mono- and diesters.

Polyethylene Glycol Glycerol Fatty Acid Esters

Preferred hydrophilic surfactants are PEG-20 glyceryl laurate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-20 glyceryl oleate, andPEG-30 glyceryl oleate.

Alcohol-Oil Transesterification Products

A large number of surfactants of different degrees of hydrophobicity orhydrophilicity can be prepared by reaction of alcohols or polyalcoholwith a variety of natural and/or hydrogenated oils. Most commonly, theoils used are castor oil or hydrogenated castor oil, or an ediblevegetable oil such as corn oil, olive oil, peanut oil, palm kernel oil,apricot kernel oil, or almond oil. Preferred alcohols include glycerol,propylene glycol, ethylene glycol, polyethylene glycol, sorbitol, andpentaerythritol. Among these alcohol-oil transesterified surfactants,preferred hydrophilic surfactants are PEG-35 castor oil (Incrocas-35),PEG-40 hydrogenated castor oil (Cremophor RH 40), PEG-25 trioleate(TAGAT® TO), PEG-60 corn glycerides (Crovol M70), PEG-60 almond oil(Crovol A70), PEG-40 palm kernel oil (Crovol PK70), PEG-50 castor oil(Emalex C-50), PEG-50 hydrogenated castor oil (Emalex HC-50), PEG-8caprylic/capric glycerides (Labrasol), and PEG-6 caprylic/capricglycerides (Softigen 767). Preferred hydrophobic surfactants in thisclass include PEG-5 hydrogenated castor oil, PEG-7 hydrogenated castoroil, PEG-9 hydrogenated castor oil, PEG-6 corn oil (Labrafil® M 2125CS), PEG-6 almond oil (Labrafil® M 1966 CS), PEG-6 apricot kernel oil(Labrafil® M 1944 CS), PEG-6 olive oil (Labrafil® M 1980 CS), PEG-6peanut oil (Labrafil® M 1969 CS), PEG-6 hydrogenated palm kernel oil(Labrafil® M 2130 BS), PEG-6 palm kernel oil (Labrafil® M 2130 CS),PEG-6 triolein (Labrafil®b M 2735 CS), PEG-8 corn oil (Labrafil® WL 2609BS), PEG-20 corn glycerides (Crovol M40), and PEG-20 almond glycerides(Crovol A40).

Polyglyceryl Fatty Acids

Polyglycerol esters of fatty acids are also suitable surfactants for usein embodiments of the present invention. Among the polyglyceryl fattyacid esters, preferred hydrophobic surfactants include polyglyceryloleate (Plurol Oleique), polyglyceryl-2 dioleate (Nikkol DGDO),polyglyceryl-10 trioleate, polyglyceryl stearate, polyglyceryl laurate,polyglyceryl myristate, polyglyceryl palmitate, and polyglyceryllinoleate. Preferred hydrophilic surfactants include polyglyceryl-10laurate (Nikkol Decaglyn 1-L), polyglyceryl-10 oleate (Nikkol Decaglyn1-0), and polyglyceryl-10 mono, dioleate (Caprol® PEG 860),polyglyceryl-10 stearate, polyglyceryl-10 laurate, polyglyceryl-10myristate, polyglyceryl-10 palmitate, polyglyceryl-10 linoleate,polyglyceryl-6 stearate, polyglyceryl-6 laurate, polyglyceryl-6myristate, polyglyceryl-6 palmitate, and polyglyceryl-6 linoleate.Polyglyceryl polyricinoleates (Polymuls) are also preferred surfactants.

Propylene Glycol Fatty Acid Esters

Esters of propylene glycol and fatty acids are suitable surfactants foruse in embodiments of the present invention. In this surfactant class,preferred hydrophobic surfactants include propylene glycol monolaurate(Lauroglycol FCC), propylene glycol ricinoleate (Propymuls), propyleneglycol monooleate (Myverol P-06), propylene glycol dicaprylate/dicaprate(Captex® 200), and propylene glycol dioctanoate (Captex® 800).

Sterol and Sterol Derivatives

Sterols and derivatives of sterols are suitable surfactants for use inembodiments of the present invention. Preferred derivatives include thepolyethylene glycol derivatives. A preferred surfactant in this class isPEG-24 cholesterol ether (Solulan C-24).

Polyethylene Glycol Sorbitan Fatty Acid Esters

A variety of PEG-sorbitan fatty acid esters are available and aresuitable for use as surfactants in embodiments of the present invention.Among the PEG-sorbitan fatty acid esters, preferred surfactants includePEG-20 sorbitan monolaurate (Tween-20), PEG-20 sorbitan monopalmitate(Tween-40), PEG-20 sorbitan monostearate (Tween-60), and PEG-20 sorbitanmonooleate (Tween-80). Laurate esters are preferred because they have ashort lipid chain compared with oleate esters, increasing drugabsorption.

Polyethylene Glycol Alkyl Ethers

Ethers of polyethylene glycol and alkyl alcohols are suitablesurfactants for use in embodiments of the present invention. Preferredethers include PEG-3 oleyl ether (Volpo 3) and PEG-4 lauryl ether (Brij30).

Sugar and Its Derivatives

Sugar derivatives are suitable surfactants for use in embodiments of thepresent invention. Preferred surfactants in this class include sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside, andoctyl-β-D-thioglucopyranoside.

Polyethylene Glycol Alkyl Phenols

Several PEG-alkyl phenol surfactants are available, such as PEG-10-100nonyl phenol and PEG-15-100 octyl phenol ether, Tyloxapol, octoxynol,nonoxynol, and are suitable for use in embodiments of the presentinvention.

Polyoxyethylene-Polyoxypropylene (POE-POP) Block Copolymers

The POE-POP block copolymers are a unique class of polymericsurfactants. The unique structure of the surfactants, with hydrophilicPOE and hydrophobic POP moieties in well-defined ratios and positions,provides a wide variety of surfactants suitable for use in embodimentsof the present invention. These surfactants are available under varioustrade names, including Synperonic PE series (ICI); Pluronic.RTM series(BASF), Emkalyx, Lutrol (BASF), Supronic, Monolan, Pluracare, andPlurodac. The generic term for these polymers is “poloxamer” (CAS9003-11-6). These polymers have the formula:

HO(C₂H₄O)_(a)(C₃H₆O)_(b)(C₂H₄O)_(a)H where “a” and “b” denote the numberof polyoxyethylene and polyoxypropylene units, respectively.

Preferred hydrophilic surfactants of this class include Poloxamers 108,188, 217, 238, 288, 338, and 407. Preferred hydrophobic surfactants inthis class include Poloxamers 124, 182, 183, 212, 331, and 335.

Sorbitan Fatty Acid Esters

Sorbitan esters of fatty acids are suitable surfactants for use inembodiments of the present invention. Among these esters, preferredhydrophobic surfactants include sorbitan monolaurate (Arlacel 20),sorbitan monopalmitate (Span-40), and sorbitan monooleate (Span-80),sorbitan monostearate.

The sorbitan monopalmitate, an amphiphilic derivative of Vitamin C(which has Vitamin C activity), can serve two important functions insolubilization systems. First, it possesses effective polar groups thatcan modulate the microenvironment. These polar groups are the samegroups that make vitamin C itself (ascorbic acid) one of the mostwater-soluble organic solid compounds available: ascorbic acid issoluble to about 30 wt/wt % in water (very close to the solubility ofsodium chloride, for example). And second, when the pH increases so asto convert a fraction of the ascorbyl palmitate to a more soluble salt,such as sodium ascorbyl palmitate.

Ionic Surfactants

Ionic surfactants, including cationic, anionic and zwitterionicsurfactants, are suitable hydrophilic surfactants for use in embodimentsof the present invention. Preferred ionic surfactants include quaternaryammonium salts, fatty acid salts and bile salts. Specifically, preferredionic surfactants include benzalkonium chloride, benzethonium chloride,cetylpyridinium chloride, docecyl trimethyl ammonium bromide, sodiumdocecylsulfates, dialkyl methylbenzyl ammonium chloride, edrophoniumchloride, domiphen bromide, dialkylesters of sodium sulfonsuccinic acid,sodium dioctyl sulfosuccinate, sodium cholate, and sodium taurocholate.These quaternary ammonium salts are preferred additives. They can bedissolved in both organic solvents (such as ethanol, acetone, andtoluene) and water. This is especially useful for medical devicecoatings because it simplifies the preparation and coating process andhas good adhesive properties. Water insoluble drugs are commonlydissolved in organic solvents.

Chemical Compounds with One or More Hydroxyl, Amino, Carbonyl, Carboxyl,Acid, Amide or Ester Moieties

The chemical compounds with one or more hydroxyl, amino, carbonyl,carboxyl, acid, amide or ester moieties include amino alcohols, hydroxylcarboxylic acid, ester, and anhydrides, hydroxyl ketone, hydroxyllactone, hydroxyl ester, sugar phosphate, sugar sulfate, ethyl oxide,ethyl glycols, amino acids, peptides, proteins, sorbitan, glycerol,polyalcohol, phosphates, sulfates, organic acids, esters, salts,vitamins, combinations of amino alcohols and organic acids, and theirsubstituted molecules. Hydrophilic chemical compounds with one or morehydroxyl, amino, carbonyl, carboxyl, acid, amide or ester moietieshaving molecular weight less than 5,000-10,000 are preferred in certainembodiments. In other embodiments, molecular weight of the additive withone or more hydroxyl, amino, carbonyl, carboxyl, acid, amide, or estermoieties is preferably less than 1000-5,000, or more preferably lessthan 750-1,000, or most preferably less than 750. In these embodiments,the molecular weight of the additive is preferred to be less than thatof the drug to be delivered. The molecular weight of the additive ispreferred to be higher than 80 since molecules with molecular weightless than 80 very easily evaporate and do not stay in the coating of amedical device. Small molecules can diffuse quickly. They can releasethemselves easily from the delivery balloon, accelerating release ofdrug, and they can diffuse away from drug when the drug binds tissue ofthe body lumen.

Fat-Soluble Vitamins and Salts Thereof

Vitamins A, D, E and K in many of their various forms and provitaminforms are considered as fat-soluble vitamins and in addition to these anumber of other vitamins and vitamin sources or close relatives are alsofat-soluble and have polar groups, and relatively high octanol-waterpartition coefficients. Clearly, the general class of such compounds hasa history of safe use and high benefit to risk ratio, making them usefulas additives in embodiments of the present invention.

The following examples of fat-soluble vitamin derivatives and/or sourcesare also useful as additives: Alpha-tocopherol, beta-tocopherol,gamma-tocopherol, delta-tocopherol, tocopherol acetate, ergosterol,1-alpha-hydroxycholecal-ciferol, vitamin D2, vitamin D3, alpha-carotene,beta-carotene, gamma-carotene, vitamin A, fursultiamine,methylolriboflavin, octotiamine, prosultiamine, riboflavine, vintiamol,dihydrovitamin K1, menadiol diacetate, menadiol dibutyrate, menadioldisulfate, menadiol, vitamin K1, vitamin K1 oxide, vitamins K2, andvitamin K-S(II). Folic acid is also of this type, and although it iswater-soluble at physiological pH, it can be formulated in the free acidform. Other derivatives of fat-soluble vitamins useful in embodiments ofthe present invention may easily be obtained via well known chemicalreactions with hydrophilic molecules.

Water-Soluble Vitamins and Their Amphiphilic Derivatives

Vitamins B, C, U, pantothenic acid, folic acid, and some of themenadione-related vitamins/provitamins in many of their various formsare considered water-soluble vitamins. These may also be conjugated orcomplexed with hydrophobic moieties or multivalent ions into amphiphilicforms having relatively high octanol-water partition coefficients andpolar groups. Again, such compounds can be of low toxicity and highbenefit to risk ratio, making them useful as additives in embodiments ofthe present invention. Salts of these can also be useful as additives inthe present invention. Examples of water-soluble vitamins andderivatives include, without limitation, acetiamine, benfotiamine,pantothenic acid, cetotiamine, cyclothiamine, dexpanthenol, niacinamide,nicotinic acid, pyridoxal 5-phosphate, nicotinamide ascorbate,riboflavin, riboflavin phosphate, thiamine, folic acid, menadioldiphosphate, menadione sodium bisulfite, menadoxime, vitamin B12,vitamin K5, vitamin K6, vitamin K6, and vitamin U. Also, as mentionedabove, folic acid is, over a wide pH range including physiological pH,water-soluble, as a salt.

Compounds in which an amino or other basic group is present can easilybe modified by simple acid-base reaction with a hydrophobicgroup-containing acid such as a fatty acid (especially lauric, oleic,myristic, palmitic, stearic, or 2-ethylhexanoic acid), low-solubilityamino acid, benzoic acid, salicylic acid, or an acidic fat-solublevitamin (such as riboflavin). Other compounds might be obtained byreacting such an acid with another group on the vitamin such as ahydroxyl group to form a linkage such as an ester linkage, etc.Derivatives of a water-soluble vitamin containing an acidic group can begenerated in reactions with a hydrophobic group-containing reactant suchas stearylamine or riboflavine, for example, to create a compound thatis useful in embodiments of the present invention. The linkage of apalmitate chain to vitamin C yields ascorbyl palmitate.

Amino Acids and Their Salts

Alanine, arginine, asparagines, aspartic acid, cysteine, cystine,glutamic acid, glutamine, glycine, histidine, proline, isoleucine,leucine, lysine, methionine, phenylalanine, serine, threonine,tryptophan, tyrosine, valine, and derivatives thereof are other usefuladditives in embodiments of the invention.

Certain amino acids, in their zwitterionic form and/or in a salt formwith a monovalent or multivalent ion, have polar groups, relatively highoctanol-water partition coefficients, and are useful in embodiments ofthe present invention. In the context of the present disclosure we take“low-solubility amino acid” to mean an amino acid which has a solubilityin unbuffered water of less than about 4% (40 mg/ml). These includeCystine, tyrosine, tryptophan, leucine, isoleucine, phenylalanine,asparagine, aspartic acid, glutamic acid, and methionine.

Amino acid dimers, sugar-conjugates, and other derivatives are alsouseful. Through simple reactions well known in the art hydrophilicmolecules may be joined to hydrophobic amino acids, or hydrophobicmolecules to hydrophilic amino acids, to make additional additivesuseful in embodiments of the present invention.

Catecholamines, such as dopamine, levodopa, carbidopa, and DOPA, arealso useful as additives.

Oligopeptides, Peptides and Proteins

Oligopeptides and peptides are useful as additives, since hydrophobicand hydrophilic amino acids may be easily coupled and various sequencesof amino acids may be tested to maximally facilitate permeation oftissue by drug.

Proteins are also useful as additives in embodiments of the presentinvention. Serum albumin, for example, is a preferred additive since itis water soluble and contains significant hydrophobic parts to binddrug: paclitaxel is 89% to 98% protein-bound after human intravenousinfusion, and rapamycin is 92% protein bound, primarily (97%) toalbumin. Furthermore, paclitaxel solubility in PBS increases over 20fold with the addition of BSA. Albumin is naturally present at highconcentrations in serum and is thus very safe for human intravascularuse.

Other useful proteins include, without limitation, other albumins,immunoglobulins, caseins, hemoglobins, lysozymes, immunoglobins,a-2-macroglobulin, fibronectins, vitronectins, firbinogens, lipases, andthe like.

Organic Acids and Their Esters and Anhydrides

Examples are acetic acid and anhydride, benzoic acid and anhydride,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,ascorbic acid, citric acid, tartaric acid, lactic acid, oxalic acidaspartic acid, nicotinic acid, 2-pyrrolidone-5-carboxylic acid, and2-pyrrolidone.

These esters and anhydrides are soluble in organic solvents such asethanol, acetone, methylethylketone, ethylacetate. The water insolubledrugs can be dissolved in organic solvent with these esters andanhydrides, then coated easily on to the medical device, then hydrolyzedunder high pH conditions. The hydrolyzed anhydrides or esters are acidsor alcohols, which are water soluble and can effectively carry the drugsoff the device into the vessel walls.

Other Chemical Compounds with One or More Hydroxyl, Amine, Carbonyl,Carboxyl, or Ester Moieties

The additives include amino alcohols, alcohols, amines, acids, amidesand hydroxyl acids in both cyclo and linear aliphatic and aromaticgroups. Examples are L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol,sorbitol, glucose, ribose, arabinose, lyxose, xylose, fructose, mannose,glucitol, sugars, sugar phosphates, glucopyranose phosphate, sugarsulphates, sinapic acid, vanillic acid, vanillin, methyl paraben, propylparaben, diethylene glycol, triethylene glycol, tetraethylene glycol,xylitol, 2-ethoxyethanol, sugars, galactose, glucose, mannose, xylose,sucrose, lactose, maltose, sorbitol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described above, polyglycidol, glycerols, and derivativesthereof.

Combinations of additives are also useful for purposes of the presentinvention.

One embodiment comprises the combination or mixture of two hydrophilicadditives, the first additive comprising a surfactant and the secondadditive comprising one of the chemical compounds with one or morehydroxyl, amine, carbonyl, carboxyl, or ester moieties

The combination or mixture of the surfactant and the small water-solublemolecule (the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties) has advantages. Formulationscomprising mixtures of the two additives with water-insoluble drug arein certain cases superior to either alone. The hydrophobic drugs bindsmall molecules more poorly than they do surfactants. They are oftenphase separated from small water-soluble molecules, which can lead tosuboptimal coating uniformity and integrity. The water-insoluble drughas Log P higher than both that of the surfactant and that of smallmolecules. However, Log P of the surfactant is typically higher than LogP of the chemical compounds with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties. The surfactant has a relatively high Log P(usually above 0) and the water soluble molecules have low Log P(usually below 0). Some surfactants, when used as additives in thepresent invention, adhere so strongly to the water-insoluble drug andthe surface of the medical device that drug is not able to rapidlyrelease from the surface of the medical device at the target site. Onthe other hand, some of the water-soluble small molecules (with one ormore hydroxyl, amine, carbonyl, carboxyl, or ester moieties) adhere sopoorly to the medical device that they release drug before it reachesthe target site, for example, into serum during the transit of a coatedballoon catheter to the site targeted for intervention. Surprisingly, byadjusting the ratio of the concentrations of the small hydrophilicmolecules, the surfactant, and the contrast agent, the coating stabilityduring transit and rapid drug release when inflated and pressed againsttissues of the lumen wall at the target site of therapeutic interventionin certain cases is superior to a formulation comprising either additiveor a contrast agent alone. Furthermore, the miscibility andcompatibility of the water-insoluble drug and the contrast agent isimproved by the presence of the surfactant. The surfactant also improvescoating uniformity and integrity by its good adhesion to the drug and tocontrast agent and to the small molecules. The long chain hydrophobicpart of the surfactant binds drug tightly to drug while the hydrophilicpart of the surfactant binds the contrast agent and also the smallmolecules.

The surfactants in the mixture or the combination include all of thesurfactants described herein for use in embodiments of the invention.The surfactant in the mixture is chosen from PEG fatty esters, PEGomega-3 fatty esters and alcohols, glycerol fatty esters, sorbitan fattyesters, PEG glyceryl fatty esters, PEG sorbitan fatty esters, sugarfatty esters, PEG sugar esters, Tween 20, Tween 40, Tween 60, Tween 80,p-isononylphenoxypolyglycidol, PEG laurate, PEG oleate, PEG stearate,PEG glyceryl laurate, PEG glyceryl oleate, PEG glyceryl stearate,polyglyceryl laurate, plyglyceryl oleate, polyglyceryl myristate,polyglyceryl palmitate, polyglyceryl-6 laurate, plyglyceryl-6 oleate,polyglyceryl-6 myristate, polyglyceryl-6 palmitate, polyglyceryl-10laurate, plyglyceryl-10 oleate, polyglyceryl-10 myristate,polyglyceryl-10 palmitate, PEG sorbitan monolaurate, PEG sorbitanmonolaurate, PEG sorbitan monooleate, PEG sorbitan stearate, PEG oleylether, PEG laurayl ether, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside and their derivatives.

The chemical compound with one or more hydroxyl, amine, carbonyl,carboxyl, or ester moieties in the mixture or the combination includeall of the chemical compounds with one or more hydroxyl, amine,carbonyl, carboxyl, or ester moieties described for use in embodimentsof the invention. The chemical compound with one or more hydroxyl,amine, carbonyl, carboxyl, or ester moieties in the mixture has at leastone hydroxyl group in one of the embodiments in the inventions. Morethan four hydroxyl groups are preferred in one embodiment. The chemicalcompound with one or more hydroxyl, amine, carbonyl, carboxyl, or estermoieties in the mixture is chosen from L-ascorbic acid and its salt,D-glucoascorbic acid and its salt, tromethamine, triethanolamine,diethanolamine, meglumine, glucamine, amine alcohols, glucoheptonicacid, glucomic acid, hydroxyl ketone, hydroxyl lactone, gluconolactone,glucoheptonolactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, ribonic acid lactone, lactobionic acid, glucosamine,glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoic acid, propyl4-hydroxybenzoate, lysine acetate salt, gentisic acid, lactobionic acid,lactitol, sorbitol, glucose, ribose, arabinose, lyxose, xylose,fructose, mannose, glucitol, sugars, sugar phosphates, glucopyranosephosphate, sugar sulphates, sinapic acid, vanillic acid, vanillin,methyl paraben, propyl paraben, diethylene glycol, triethylene glycol,tetraethylene glycol, xylitol, 2-ethoxyethanol, sugars, galactose,glucose, mannose, xylose, sucrose, lactose, maltose, cyclodextrin,sorbitol, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine described above, polyglycidol,glycerols, and derivatives thereof.

Preferred additives include p-isononylphenoxypolyglycidol, PEG glyceryloleate, PEG glyceryl stearate, polyglyceryl laurate, plyglyceryl oleate,polyglyceryl myristate, polyglyceryl palmitate, polyglyceryl-6 laurate,plyglyceryl-6 oleate, polyglyceryl-6 myristate, polyglyceryl-6palmitate, polyglyceryl-10 laurate, plyglyceryl-10 oleate,polyglyceryl-10 myristate, polyglyceryl-10 palmitate, PEG sorbitanmonolaurate, PEG sorbitan monolaurate, PEG sorbitan monooleate, PEGsorbitan stearate, octoxynol, monoxynol, tyloxapol, sucrosemonopalmitate, sucrose monolaurate, decanoyl-N-methylglucamide,n-decyl-β-D-glucopyranoside, n-decyl-β-D-maltopyranoside,n-dodecyl-β-D-glucopyranoside, n-dodecyl-β-D-maltoside,heptanoyl-N-methylglucamide, n-heptyl-β-D-glucopyranoside,n-heptyl-β-D-thioglucoside, n-hexyl-β-D-glucopyranoside,nonanoyl-N-methylglucamide, n-noyl-β-D-glucopyranoside,octanoyl-N-methylglucamide, n-octyl-β-D-glucopyranoside,octyl-β-D-thioglucopyranoside; cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine (amino acids); cetotiamine; cyclothiamine, dexpanthenol,niacinamide, nicotinic acid and its salt, pyridoxal 5-phosphate,nicotinamide ascorbate, riboflavin, riboflavin phosphate, thiamine,folic acid, menadiol diphosphate, menadione sodium bisulfite,menadoxime, vitamin B12, vitamin K5, vitamin K6, vitamin K6, and vitaminU (vitamins); albumin, immunoglobulins, caseins, hemoglobins, lysozymes,immunoglobins, a-2-macroglobulin, fibronectins, vitronectins,firbinogens, lipases, benzalkonium chloride, benzethonium chloride,docecyl trimethyl ammonium bromide, sodium docecylsulfates, dialkylmethylbenzyl ammonium chloride, and dialkylesters of sodiumsulfonsuccinic acid, L-ascorbic acid and its salt, D-glucoascorbic acidand its salt, tromethamine, triethanolamine, diethanolamine, meglumine,glucamine, amine alcohols, glucoheptonic acid, glucomic acid, hydroxylketone, hydroxyl lactone, gluconolactone, glucoheptonolactone,glucooctanoic lactone, gulonic acid lactone, mannoic lactone, ribonicacid lactone, lactobionic acid, glucosamine, glutamic acid, benzylalcohol, benzoic acid, hydroxybenzoic acid, propyl 4-hydroxybenzoate,lysine acetate salt, gentisic acid, lactobionic acid, lactitol, sinapicacid, vanillic acid, vanillin, methyl paraben, propyl paraben, sorbitol,cyclodextrin, (2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen,retinoic acid, lysine acetate, gentisic acid, catechin, catechingallate, tiletamine, ketamine, propofol, lactic acids, acetic acid,salts of any organic acid and amine described above, polyglycidol,glycerols, and derivatives thereof. (chemical compounds with one or morehydroxyl, amino, carbonyl, carboxyl, or ester moieties). Some of theseadditives are both water-soluble and organic solvent-soluble. They havegood adhesive properties and adhere to the surface of polyamide medicaldevices, such as balloon catheters. They may therefore be used in theadherent layer, top layer, and/or in the drug layer of embodiments ofthe present invention. The aromatic and aliphatic groups increase thesolubility of water insoluble drugs in the coating solution, and thepolar groups of alcohols and acids bind contrast agent and improve thephysical properties of the coating layer overlying the medical deviceand accelerate drug release from the device and drug permeation intotissue during deployment.

Other preferred additives according to embodiments of the inventioninclude the combination of an amino alcohol and an organic acid.Examples are lysine/glutamic acid, lysine acetate, lactobionicacid/meglumine, lactobionic acid/tromethanemine, lactobionicacid/diethanolamine, lactic acid/meglumine, lactic acid/tromethanemine,lactic acid/diethanolamine, gentisic acid/meglumine, gentisicacid/tromethanemine, gensitic acid/diethanolamine, vanillicacid/meglumine, vanillic acid/tromethanemine, vanillicacid/diethanolamine, benzoic acid/meglumine, benzoicacid/tromethanemine, benzoic acid/diethanolamine, acetic acid/meglumine,acetic acid/tromethanemine, and acetic acid/diethanolamine.

Other preferred additives according to embodiments of the inventioninclude hydroxyl ketone, hydroxyl lactone, hydroxyl acid, hydroxylester, and hydroxyl amide. Examples are gluconolactone,D-glucoheptono-1,4-lactone, glucooctanoic lactone, gulonic acid lactone,mannoic lactone, erythronic acid lactone, ribonic acid lactone,glucuronic acid, gluconic acid, gentisic acid, lactobionic acid, lacticacid, acetaminophen, vanillic acid, sinapic acid, hydroxybenzoic acid,methyl paraben, propyl paraben, and derivatives thereof.

Other preferred additives that may be useful in embodiments of thepresent invention include riboflavin, riboflavin-phosphate sodium,Vitamin D3, folic acid (vitamin B9), vitamin 12,diethylenetriaminepentaacetic acid dianhydride,ethylenediaminetetraacetic dianhydride, maleic acid and anhydride,succinic acid and anhydride, diglycolic anhydride, glutaric anhydride,L-ascorbic acid, thiamine, nicotinamide, nicotinic acid,2-pyrrolidone-5-carboxylic acid, cystine, tyrosine, tryptophan, leucine,isoleucine, phenylalanine, asparagine, aspartic acid, glutamic acid, andmethionine and octyl-β-D-thioglucopyranoside.

From a structural point of view, these additives share structuralsimilarities and are compatible with water insoluble drugs (such aspaclitaxel and rapamycin). They often contain double bonds such as C═C,C═N, C═O in aromatic or aliphatic structures. These additives alsocontain amine, alcohol, ester, amide, anhydride, carboxylic acid, and/orhydroxyl groups. They may form hydrogen bonds and/or charge and/or vander Waals interactions with drug. They may also form hydrogen bonds withand have affinity for contrast agent. They are also useful in the toplayer in the coating. Compounds containing one or more hydroxyl,carboxyl, or amine groups, for example, are especially useful asadditives since they facilitate drug release from the device surface andeasily displace water next to the polar head groups and surface proteinsof cell membranes and may thereby remove this barrier to hydrophobicdrug permeability. They accelerate movement of a hydrophobic drug offthe balloon to the lipid layer of cell membranes and tissues for whichit has very high affinity. They may also carry or accelerate themovement of drug off the balloon into more aqueous environments such asthe interstitial space, for example, of vascular tissues that have beeninjured by balloon angioplasty or stent expansion. Additives such aspolyglyceryl fatty esters, ascorbic ester of fatty acids, sugar esters,alcohols and ethers of fatty acids have fatty chains that can integrateinto the lipid structure of target tissue membranes, carrying drug tolipid structures. Some of the amino acids, vitamins and organic acidshave aromatic C═N groups as well as amino, hydroxyl, and carboxyliccomponents to their structure. They have structural parts that can bindor complex with hydrophobic drug, such as paclitaxel or rapamycin, andthey also have structural parts that facilitate tissue penetration byremoving barriers between hydrophobic drug and lipid structure of cellmembranes.

For example, isononylphenylpolyglycidol (Olin-10 G and Surfactant-10G),PEG glyceryl monooleate, sorbitan monolaurate (Arlacel 20), sorbitanmonopalmitate (Span-40), sorbitan monooleate (Span-80), sorbitanmonostearate, polyglyceryl-10 oleate, polyglyceryl-10 laurate,polyglyceryl-10 palmitate, and polyglyceryl-10 stearate all have morethan four hydroxyl groups in their hydrophilic part. These hydroxylgroups have very good affinity for the vessel wall and can displacehydrogen-bound water molecules. At the same time, they have long chainsof fatty acid, alcohol, ether and ester that can both complex withhydrophobic drug and integrate into the lipid structure of the cellmembranes to form the part of the lipid structure. This deformation orloosening of the lipid membrane of target cells may further acceleratepermeation of hydrophobic drug into tissue.

For another example, L-ascorbic acid, thiamine, maleic acids,niacinamide, and 2-pyrrolidone-5-carboxylic acid all have a very highwater and ethanol solubility and a low molecular weight and small size.They also have structural components including aromatic C═N, amino,hydroxyl, and carboxylic groups. These structures have very goodcompatibility with paclitaxel and rapamycin and can increase thesolubility of these water-insoluble drugs in water and enhance theirabsorption into tissues. However, they often have poor adhesion to thesurface of medical devices. They are therefore preferably used incombination with other additives in the drug layer and top layer wherethey are useful to enhance drug absorption. Vitamin D2 and D3 areespecially useful because they themselves have anti-restenotic effectsand reduce thrombosis, especially when used in combination withpaclitaxel.

In one embodiment of the present invention, the additive is soluble inaqueous solvents and is soluble in organic solvents.

Oil, Fatty Acid and Lipid

In one embodiment, the coating layer overlying the surface of a medicaldevice is comprised of a lipophilic or water-insoluble therapeuticagent, a contrast agent, and one of an oil, a fatty acid, and a lipid.In one embodiment, a solution for coating the surface of a medicaldevice is comprised of a lipophilic or water-insoluble therapeuticagent, a contrast agent, and one of an oil, a fatty acid, and a lipid.In one embodiment, a pharmaceutical preparation is comprised of alipophilic or water-insoluble therapeutic agent, a contrast agent, andone of an oil, a fatty acid, and a lipid, wherein the therapeutic agentis not encapsulated by liposomes or particles. In one embodiment, theone of an oil, a fatty acid, and a lipid is interdispersed with thelipophilic or water-insoluble drug and the contrast agent in the coatingof a medical device. In certain embodiments, the contrast agent maydisrupt the hydrophobic attractions between lipophilic drug and itselfand the one of an oil, fatty acid, and lipid and the surface of themedical device and accelerate elution of the therapeutic agent off thedevice.

In these embodiments, the oil, the fatty acid and the lipid arehydrophobic. They are not soluble in water. The lipophilic orwater-insoluble therapeutic agents, such as paclitaxel, rapamycin andtheir analogues, are soluble in the oil, fatty acid and lipid. The oil,fatty acid and lipid in embodiments of the invention herein include, forexample, soybean oil, vegetable oil, flower oil, animal oil, marine oil,butterfat, coconut oil, palm oil, olive oil, peanut oil, fish oil,butanoic acid, hexanoic acid, octanoic acid, decanoic acid, dodecanoicacid, tetradecanoic acid, hexadecanoic acid, octadecanoic acid,octadecatrienoic acid, eicosanoic acid, eicosenoic acid,eicosatetraenoic acid, eicosapentaenoic acid, docosahexaenoic acid,tocotrienol, butyric acid, caproic acid, caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearicacid, oleic acid, vaccenic acid, linoleic acid, alpha-linolenic acid,gamma-linolenic acid, behenic acid, erucic acid, lignoceric acid,natural or synthetic phospholipids, mono-, di-, or triacylglycerols,cardiolipin, phosphatidylglycerol, phosphatidic acid,phosphatidylcholine, alpha tocoferol, phosphatidylethanolamine,sphingomyelin, phosphatidylserine, phosphatidylinositol,dimyristoylphosphatidylcholine, dioleoylphosphatidylcholine,dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine,phosphatidylethanolamines phosphatidylglycerols, sphingolipids,prostaglandins, gangliosides, neobee, niosomes and derivatives.

There are many other oils, fatty acids, and lipids known in the art thatare useful in embodiments of the present invention.

In one embodiment, the concentration density of the at least onetherapeutic agent applied to the surface of the medical device is fromabout 1 to 20 μg/mm², or more preferably from about 2 to 6 μg/mm². Inone embodiment, the concentration of the at least one additive appliedto the surface of the medical device is from about 1 to 20 μg/mm². Inone embodiment, the concentration of the contrast agent applied to thesurface of the medical device is from about 1 to 20 μg/mm². The ratio ofadditive to drug by weight in the coating layer in embodiments of thepresent invention is about 0.05 to 20, preferably about 0.5 to 10, ormore preferably about 0.8 to 5.

The relative amount of the therapeutic agent, the contrast agent, andthe additive in the coating layer may vary depending on applicablecircumstances. The optimal amount of the additive can depend upon, forexample, the particular therapeutic agent and contrast agent andadditive selected, the critical micelle concentration of the surfacemodifier, the hydrophilic-lipophilic-balance (HLB) of a surfactant or anadditive's the octonol-water partition coefficient (P), the meltingpoint of the additive, the water solubility of the additive and/ortherapeutic agent, the surface tension of water solutions of the surfacemodifier, etc.

The additives are present in exemplary coating compositions ofembodiments of the present invention in amounts such that upon dilutionwith an aqueous solution, the carrier forms a clear, aqueous dispersionor emulsion or solution, containing the hydrophobic therapeutic agent inaqueous and organic solutions. When the relative amount of surfactant istoo great, the resulting dispersion is visibly “cloudy”.

The optical clarity of the aqueous dispersion can be measured usingstandard quantitative techniques for turbidity assessment. Oneconvenient procedure to measure turbidity is to measure the amount oflight of a given wavelength transmitted by the solution, using, forexample, an UV-visible spectrophotometer. Using this measure, opticalclarity corresponds to high transmittance, since cloudier solutions willscatter more of the incident radiation, resulting in lower transmittancemeasurements.

Another method of determining optical clarity and carrier diffusivitythrough the aqueous boundary layer is to quantitatively measure the sizeof the particles of which the dispersion is composed. These measurementscan be performed on commercially available particle size analyzers.

Other considerations will further inform the choice of specificproportions of different additives and contrast agent and drug. Theseconsiderations include the degree of bioacceptability of the additivesand the desired dosage of hydrophobic therapeutic agent to be provided.

Therapeutic Agent

The drugs or biologically active materials, which can be used inembodiments of the present invention, can be any therapeutic agent orsubstance. The drugs can be of various physical states, e.g., moleculardistribution, crystal forms or cluster forms. Examples of drugs that areespecially useful in embodiments of the present invention are lipophilicsubstantially water insoluble drugs, such as paclitaxel, rapamycin,daunorubicin, doxorubicin, lapachone, vitamin D2 and D3 and analoguesand derivatives thereof. These drugs are especially suitable for use ina coating on a balloon catheter used to treat tissue of the vasculature.

Other drugs that may be useful in embodiments of the present inventioninclude, without limitation, glucocorticoids (e.g., dexamethasone,betamethasone), hirudin, angiopeptin, aspirin, growth factors, antisenseagents, anti-cancer agents, anti-proliferative agents, oligonucleotides,and, more generally, anti-platelet agents, anti-coagulant agents,anti-mitotic agents, antioxidants, anti-metabolite agents,anti-chemotactic, and anti-inflammatory agents.

Also useful in embodiments of the present invention are polynucleotides,antisense, RNAi, or siRNA, for example, that inhibit inflammation and/orsmooth muscle cell or fibroblast proliferation.

Anti-platelet agents can include drugs such as aspirin and dipyridamole.Aspirin is classified as an analgesic, antipyretic, anti-inflammatoryand anti-platelet drug. Dipyridamole is a drug similar to aspirin inthat it has anti-platelet characteristics. Dipyridamole is alsoclassified as a coronary vasodilator. Anti-coagulant agents for use inembodiments of the present invention can include drugs such as heparin,protamine, hirudin and tick anticoagulant protein. Anti-oxidant agentscan include probucol. Anti-proliferative agents can include drugs suchas amlodipine and doxazosin. Anti-mitotic agents and anti-metaboliteagents that can be used in embodiments of the present invention includedrugs such as methotrexate, azathioprine, vincristine, vinblastine,5-fluorouracil, adriamycin, and mutamycin. Antibiotic agents for use inembodiments of the present invention include penicillin, cefoxitin,oxacillin, tobramycin, and gentamicin. Suitable antioxidants for use inembodiments of the present invention include probucol. Additionally,genes or nucleic acids, or portions thereof can be used as thetherapeutic agent in embodiments of the present invention. Furthermore,collagen-synthesis inhibitors, such as tranilast, can be used as atherapeutic agent in embodiments of the present invention.

Photosensitizing agents for photodynamic or radiation therapy, includingvarious porphyrin compounds such as porfimer, for example, are alsouseful as drugs in embodiments of the present invention.

Drugs for use in embodiments of the present invention also includeeverolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin,ascomycin, bafilomycin, erythromycin, midecamycin, josamycin,concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin,simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin,pravastatin, pitavastatin, vinblastine, vincristine, vindesine,vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine,cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan,ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine,busulfan, procarbazine, treosulfan, temozolomide, thiotepa,daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone,idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate,fludarabine, fludarabine-5′-dihydrogenphosphate, cladribine,mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine,capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine,irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin,aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole,exemestane, letrozole, formestane, aminoglutethimide, adriamycin,azithromycin, spiramycin, cepharantin, smc proliferation inhibitor-2w,epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil,c-myc-antisense, b-myc-antisense, betulinic acid, camptothecin,lapachol, beta.-lapachone, podophyllotoxin, betulin, podophyllic acid2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferon a-2b,lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab,daclizumab, selectin (cytokine antagonist), CETP inhibitor, cadherines,cytokinin inhibitors, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin,camptothecin, fluoroblastin, monoclonal antibodies, which inhibit themuscle cell proliferation, bFGF antagonists, probucol, prostaglandins,1,11-dimethoxycanthin-6-one, 1-hydroxy-11-methoxycanthin-6-one,scopoletin, colchicine, NO donors such as pentaerythritol tetranitrateand syndnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine,beta.-estradiol, a-estradiol, estriol, estrone, ethinylestradiol,fosfestrol, medroxyprogesterone, estradiol cypionates, estradiolbenzoates, tranilast, kamebakaurin and other terpenoids, which areapplied in the therapy of cancer, verapamil, tyrosine kinase inhibitors(tyrphostines), cyclosporine A, 6-a-hydroxy-paclitaxel, baccatin,taxotere and other macrocyclic oligomers of carbon suboxide (MCS) andderivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac,dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamicacid, piroxicam, meloxicam, chloroquine phosphate, penicillamine,hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol,celecoxib, .beta.-sitosterin, ademetionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine, D-24851(Calbiochem), colcemid, cytochalasin A-E, indanocine, nocodazole, S 100protein, bacitracin, vitronectin receptor antagonists, azelastine,guanidyl cyclase stimulator tissue inhibitor of metal proteinase-1 and-2, free nucleic acids, nucleic acids incorporated into virustransmitters, DNA and RNA fragments, plasminogen activator inhibitor-1,plasminogen activator inhibitor-2, antisense oligonucleotides, VEGFinhibitors, IGF-1, active agents from the group of antibiotics such ascefadroxil, cefazolin, cefaclor, cefotaxim, tobramycin, gentamycin,penicillins such as dicloxacillin, oxacillin, sulfonamides,metronidazol, antithrombotics such as argatroban, aspirin, abciximab,synthetic antithrombin, bivalirudin, coumadin, enoxaparin, desulphatedand N-reacetylated heparin, tissue plasminogen activator, Gpllb/Illaplatelet membrane receptor, factor Xa inhibitor antibody, heparin,hirudin, r-hirudin, PPACK, protamin, prourokinase, streptokinase,warfarin, urokinase, vasodilators such as dipyramidole, trapidil,nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin,ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril,losartan, thiolprotease inhibitors, prostacyclin, vapiprost, interferona, .beta and y, histamine antagonists, serotonin blockers, apoptosisinhibitors, apoptosis regulators such as p65 NF-kB or Bcl-xL antisenseoligonucleotides, halofuginone, nifedipine, tranilast, molsidomine, teapolyphenols, epicatechin gallate, epigallocatechin gallate, Boswellicacids and derivatives thereof, leflunomide, anakinra, etanercept,sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone,mutamycin, procainamide, retinoic acid, quinidine, disopyramide,flecamide, propafenone, sotalol, amidorone, natural and syntheticallyobtained steroids such as bryophyllin A, inotodiol, maquiroside A,ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone,dexamethasone, non-steroidal substances (NSAIDS) such as fenoprofen,ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviralagents such as acyclovir, ganciclovir and zidovudine, antimycotics suchas clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole,nystatin, terbinafine, antiprozoal agents such as chloroquine,mefloquine, quinine, moreover natural terpenoids such as hippocaesculin,barringtogenol-C21-angelate, 14-dehydroagrostistachin, agroskerin,agrostistachin, 17-hydroxyagrostistachin, ovatodiolids,4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3 and B7,tubeimoside, bruceanol A, B and C, bruceantinoside C, yadanziosides Nand P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A, B, Cand D, ursolic acid, hyptatic acid A, zeorin, iso-iridogermanal,maytenfoliol, effusantin A, excisanin A and B, longikaurin B,sculponeatin C, kamebaunin, leukamenin A and B,13,18-dehydro-6-a-senecioyloxychaparrin, taxamairin A and B, regenilol,triptolide, moreover cymarin, apocymarin, aristolochic acid, anopterin,hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburinchloride, cictoxin, sinococuline, bombrestatin A and B, cudraisoflavoneA, curcumin, dihydronitidine, nitidine chloride,12-beta-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid,helenalin, indicine, indicine-N-oxide, lasiocarpine, inotodiol,glycoside 1a, podophyllotoxin, justicidin A and B, larreatin,malloterin, mallotochromanol, isobutyrylmallotochromanol, maquiroside A,marchantin A, maytansine, lycoridicin, margetine, pancratistatin,liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII,bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid,deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid,methylsorbifolin, sphatheliachromen, stizophyllin, mansonine,strebloside, akagerine, dihydrousambarensine, hydroxyusambarine,strychnopentamine, strychnophylline, usambarine, usambarensine,berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol,methoxylariciresinol, syringaresinol, umbelliferon, afromoson,acetylvismione B, desacetylvismione A, and vismione A and B.

A combination of drugs can also be used in embodiments of the presentinvention. Some of the combinations have additive effects because theyhave a different mechanism, such as paclitaxel and rapamycin, paclitaxeland active vitamin D, paclitaxel and lapachone, rapamycin and activevitamin D, rapamycin and lapachone. Because of the additive effects, thedose of the drug can be reduced as well. These combinations may reducecomplications from using a high dose of the drug.

Adherent Layer

The adherent layer, which is an optional layer underlying the drugcoating layer, improves the adherence of the drug coating layer to theexterior surface of the medical device and protects coating integrity.If drug, contrast agent, and additive differ in their adherence to themedical device, the adherent layer may prevent differential loss (duringtransit) or elution (at the target site) of drug layer components inorder to maintain consistent drug-to-additive or drug-to-drug ordrug-to-contrast agent ratio in the drug layer and therapeutic deliveryat the target site of intervention. Furthermore, the adherent layer mayfunction to facilitate release of coating layer components whichotherwise might adhere too strongly to the device for elution duringbrief contact with tissues at the target site. For example, in the casewhere a particular drug binds the medical device tightly, morehydrophilic components are incorporated into the adherent layer in orderto decrease affinity of the drug to the device surface.

The adherent layer may also comprise one or more of the additivespreviously described, contrast agent, or other components, in order tomaintain the integrity and adherence of the coating layer to the deviceand to facilitate both adherence of drug, contrast agent, and additivecomponents during transit and rapid elution during deployment at thesite of therapeutic intervention.

Top Layer

In order to further protect the integrity of the drug layer, an optionaltop layer may be applied to prevent loss of drug during transit throughtortuous anatomy to the target site or during the initial expansion ofthe device before the coating makes direct contact with target tissue.The top layer may release slowly in the body lumen while protecting thedrug layer. The top layer will erode more slowly if it is comprised ofmore hydrophobic, high molecular weight additives. Surfactants areexamples of more hydrophobic structures with long fatty chains, such asTween 20, Tween 40, Tween 60, Tween 80, and polyglyceryl oleate. Highmolecular weight additives include polyethylene oxide, polyethyleneglycol, and polyvinyl pyrrolidone. Hydrophobic drug itself can act as atop layer component. For example, paclitaxel or rapamycin arehydrophobic. They can be used in the top layer. On the other hand, thetop layer cannot erode too slowly or it might actually slow the releaseof drug during deployment at the target site. Other additives useful inthe top coat include additives that strongly interact with drug or withthe coating layer, such as L-ascorbic acid and its salt, D-glucoascorbicacid and its salt, tromethamine, triethanolamine, diethanolamine,meglumine, glucamine, amine alcohols, glucoheptonic acid, glucomic acid,gluconolactone, glucosamine, glutamic acid, benzyl alcohol, benzoicacid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetatesalt, gentisic acid, lactobionic acid, lactitol, sinapic acid, vanillicacid, vanillin, methyl paraben, propyl paraben, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, lactic acids, acetic acid, salts of any organic acidand amine described above, polyglycidol, glycerols, multiglycerols, andderivatives thereof.

Solvents

Solvents for preparing of the coating layer may include, as examples,any combination of one or more of the following: (a) water, (b) alkanessuch as hexane, octane, cyclohexane, and heptane, (c) aromatic solventssuch as benzene, toluene, and xylene, (d) alcohols such as ethanol,propanol, and isopropanol, diethylamide, ethylene glycol monoethylether, Trascutol, and benzyl alcohol (e) ethers such as dioxane,dimethyl ether and tetrahydrofuran, (f) esters/acetates such as ethylacetate and isobutyl acetate, (g) ketones such as acetone, acetonitrile,diethyl ketone, and methyl ethyl ketone, and (h) mixture of water andorganic solvents such as water/ethanol, water/acetone, water/methanol,water/tetrahydrofuran.

Organic solvents, such as short-chained alcohol, dioxane,tetrahydrofuran, dimethylformamide, acetonitrile, dimethylsulfoxide,etc., are particularly useful and preferred solvents in embodiments ofthe present invention because these organic solvents generally disruptcollodial aggregates and co-solubilize all the components in the coatingsolution.

The therapeutic agent, contrast agent, and additive or additives may bedispersed in, solubilized, or otherwise mixed in the solvent. The weightpercent of drug and contrast agent and additives in the solvent may bein the range of 0.1-80% by weight, preferably 2-20% by weight.

Another embodiment of the invention relates to a method for preparing amedical device, particularly, for example, a balloon catheter or astent. First, a coating solution or suspension comprising at least onesolvent, at least one therapeutic agent, at least one contrast agent,and at least one additive is prepared. In at least one embodiment, thecoating solution or suspension includes only these four components. Thecontent of the therapeutic agent in the coating solution can be from0.5-50% by weight based on the total weight of the solution. The contentof the contrast agent or of the additive in the coating solution can befrom 1-45% by weight, 1 to 40% by weight, or from 1-15% by weight basedon the total weight of the solution. The amount of solvent used dependson the coating process and viscosity. It will affect the uniformity ofthe drug-additive/contrast agent coating but will be evaporated.

In other embodiments, two or more solvents, two or more therapeuticagents, and/or two or more contrast agents, and/or two or more additivesmay be used in the coating solution.

Various techniques may be used for applying a coating solution to amedical device such as casting, spinning, spraying, dipping (immersing),ink jet printing, electrostatic techniques, and combinations of theseprocesses. Choosing an application technique principally depends on theviscosity and surface tension of the solution. In embodiments of thepresent invention, dipping and spraying are preferred because it makesit easier to control the uniformity of the thickness of the coatinglayer as well as the concentration of the therapeutic agent applied tothe medical device. Regardless of whether the coating is applied byspraying or by dipping or by another method or combination of methods,each layer is usually deposited on the medical device in multipleapplication steps in order to control the uniformity and the amount oftherapeutic substance and additive applied to the medical device.

Each applied layer is from about 0.1 microns to 15 microns in thickness.The total number of layers applied to the medical device is in a rangeof from about 2 to 50. The total thickness of the coating is from about2 to 200 microns.

As discussed above, spraying and dipping are particularly useful coatingtechniques for use in embodiments of the present invention. In aspraying technique, a coating solution or suspension of an embodiment ofthe present invention is prepared and then transferred to an applicationdevice for applying the coating solution or suspension to a ballooncatheter.

An application device that may be used is a paint jar attached to an airbrush, such as a Badger Model 150, supplied with a source of pressurizedair through a regulator (Norgren, 0-160 psi). When using such anapplication device, once the brush hose is attached to the source ofcompressed air downstream of the regulator, the air is applied. Thepressure is adjusted to approximately 15-25 psi and the nozzle conditionchecked by depressing the trigger.

Prior to spraying, both ends of the relaxed balloon are fastened to thefixture by two resilient retainers, i.e., alligator clips, and thedistance between the clips is adjusted so that the balloon remained in adeflated, folded, or an inflated or partially inflated, unfoldedcondition. The rotor is then energized and the spin speed adjusted tothe desired coating speed, about 40 rpm.

With the balloon rotating in a substantially horizontal plane, the spraynozzle is adjusted so that the distance from the nozzle to the balloonis about 1-4 inches. First, the coating solution is sprayedsubstantially horizontally with the brush being directed along theballoon from the distal end of the balloon to the proximal end and thenfrom the proximal end to the distal end in a sweeping motion at a speedsuch that one spray cycle occurred in about three balloon rotations. Theballoon is repeatedly sprayed with the coating solution, followed bydrying, until an effective amount of the drug is deposited on theballoon.

In one embodiment of the present invention, the balloon is inflated orpartially inflated, the coating solution is applied to the inflatedballoon, for example by spraying, and then the balloon is deflated andfolded before drying. Drying may be performed under vacuum.

It should be understood that this description of an application device,fixture, and spraying technique is exemplary only. Any other suitablespraying or other technique may be used for coating the medical device,particularly for coating the balloon of a balloon catheter or stentdelivery system or stent.

After the medical device is sprayed with the coating solution, thecoated balloon is subjected to a drying in which the solvent in thecoating solution is evaporated. This produces a coating matrix on theballoon containing the therapeutic agent. One example of a dryingtechnique is placing a coated balloon into an oven at approximately 20°C. or higher for approximately 24 hours. Any other suitable method ofdrying the coating solution may be used. The time and temperature mayvary with particular additives and therapeutic agents.

Optional Post Treatment

After depositing the drug-additive containing layer on the device ofcertain embodiments of the present invention, dimethyl sulfoxide (DMSO)or other solvent may be applied, by dip or spray or other method, to thefinished surface of the coating. DMSO readily dissolves drugs and easilypenetrates membranes and may enhance tissue absorption.

It is contemplated that the medical devices of embodiments of thepresent invention have applicability for treating blockages andocclusions of any body passageways, including, among others, thevasculature, including coronary, peripheral, and cerebral vasculature,the gastrointestinal tract, including the esophagus, stomach, smallintestine, and colon, the pulmonary airways, including the trachea,bronchi, bronchioles, the sinus, the biliary tract, the urinary tract,prostate and brain passages. They are especially suited for treatingtissue of the vasculature with, for example, a balloon catheter or astent.

Yet another embodiment of the present invention relates to a method oftreating a blood vessel. The method includes inserting a medical devicecomprising a coating into a blood vessel. The coating layer comprises atherapeutic agent, a contrast agent, and an additive. In thisembodiment, the medical device can be configured as having at least anexpandable portion. Some examples of such devices include ballooncatheters, perfusion balloon catheters, cutting balloon catheters,scoring balloon catheters, self-expanded and balloon expanded-stents,guide catheters, guide wires, embolic protection devices, and variousimaging devices.

As mentioned above, one example of a medical device that is particularlyuseful in the present invention is a coated balloon catheter. A ballooncatheter typically has a long, narrow, hollow tube tabbed with aminiature, deflated balloon. In embodiments of the present invention,the balloon is coated with a drug solution. Then, the balloon ismaneuvered through the cardiovascular system to the site of a blockage,occlusion, or other tissue requiring a therapeutic agent. Once in theproper position, the balloon is inflated and contacts the walls of theblood vessel and/or a blockage or occlusion. It is an object ofembodiments of the present invention to rapidly deliver drug to andfacilitate absorption by target tissue. It is advantageous toefficiently deliver drug to tissue in as brief a period of time aspossible while the device is deployed at the target site. Thetherapeutic agent is released into such tissue, for example the vesselwalls, in about 0.1 to 30 minutes, for example, or preferably about 0.1to 10 minutes, or more preferably about 0.2 to 2 minutes, or mostpreferably, about 0.1 to 1 minutes, of balloon inflation time pressingthe drug coating into contact with diseased vascular tissue.

Further, the balloon catheter may be used to treat vasculartissue/disease alone or in combination with other methods for treatingthe vasculature, for example, photodynamic therapy or atherectomy.Atherectomy is a procedure to remove plaque from arteries. Specifically,atherectomy removes plaque from peripheral and coronary arteries. Themedical device used for peripheral or coronary atherectomy may be alaser catheter or a rotablator or a direct atherectomy device on the endof a catheter. The catheter is inserted into the body and advancedthrough an artery to the area of narrowing. After the atherectomy hasremoved some of the plaque, balloon angioplasty using the coated balloonof embodiments of the present invention may be performed. In addition,stenting may be performed thereafter, or simultaneous with expansion ofthe coated balloon as described above. Photodynamic therapy is aprocedure where light or irradiated energy is used to kill target cellsin a patient. A light-activated photosensitizing drug may be deliveredto specific areas of tissue by embodiments of the present invention. Atargeted light or radiation source selectively activates the drug toproduce a cytotoxic response and mediate a therapeuticanti-proliferative effect.

In some of the embodiments of drug and contrast agent-containingcoatings and layers according to the present invention, however, thecoating or layer does not include polymers, oils, or lipids. And,furthermore, the therapeutic agent is not encapsulated in polymerparticles, micelles, or liposomes. As described above, such formulationshave significant disadvantages and can inhibit the intended efficient,rapid release and tissue penetration of the agent, especially in theenvironment of diseased tissue of the vasculature.

Although various embodiments are specifically illustrated and describedherein, it will be appreciated that modifications and variations of thepresent invention are covered by the above teachings and are within thepurview of the appended claims without departing from the spirit andintended scope of the invention.

Unless otherwise indicated, all numbers expressing quantities ofcomponents in a layer, reaction conditions, and so forth used in thespecification and claims are to be understood as being modified in allinstances by the term “about.” Accordingly, unless otherwise indicatedto the contrary, the numerical parameters set forth in thisspecification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent disclosure.

Preparation

The medical device and the coating layers of embodiments of the presentinvention can be made according to various methods. For example, thecoating solution can be prepared by dispersing, dissolving, diffusing,or otherwise mixing all the ingredients, such as a therapeutic agent, acontrast agent, an additive, and a solvent, simultaneously together.Also, the coating solution can be prepared by sequentially adding eachcomponent based on solubility or any other parameters. For example, thecoating solution can be prepared by first adding the therapeutic agentto the solvent and then adding the additive and the contrast agent.Alternatively, the additive and the contrast agent can be added to thesolvent first and then the therapeutic agent can be later added. If thesolvent used does not sufficiently dissolve the drug, it is preferableto first add the additive to the solvent, then the drug, since theadditive will increase drug solubility in the solvent.

EXAMPLES

The following examples include embodiments of medical devices andcoating layers within the scope of the present invention. While thefollowing examples are considered to embody the present invention, theexamples should not be interpreted as limitations upon the presentinvention.

Example 1 Preparation of Coating Solutions

Formulation 1—50-100 mg (0.06-0.12 mmole) paclitaxel, 1-1.6 ml acetone,1-1.6 ml ethanol, 50-100 mg iopromide, and 50-100 mg Tween 20 are mixed.

Formulation 2—50-100 mg (0.06-0.12 mmole) paclitaxel, 1-1.6 ml acetone,1-1.6 ml ethanol, 50-100 mg iopromide, and 50-100 mg Tween 40 are mixed.

Formulation 3—50-100 mg (0.05-0.11 mmole) rapamycin, 1-1.6 ml acetone,1-1.6 ml ethanol, 50-100 mg iopromide, and 50-100 mg Tween 20 are mixed.

Formulation 4—50-100 mg (0.05-0.11 mmole) rapamycin, 0.5-1.0 ml acetone,0.5-1.0 ml ethanol, 5-35 mg iopromide, and 35-70 mg Tween 40 are mixed.

Formulation 5—50-100 mg (0.06-0.12 mmole) paclitaxel, 1-1.6 ml acetone,1-1.6 ml ethanol, 50-100 mg loversol, and 50-100 mg Tween 20 are mixed.

Formulation 6—50-100 mg (0.06-0.12 mmole) paclitaxel, 1-1.6 ml acetone,1-1.6 ml ethanol, 50-100 mg loversol, and 50-100 mg Tween 40 are mixed.

Formulation 7—50-100 mg (0.05-0.11 mmole) rapamycin, 1-1.6 ml acetone,1-1.6 ml ethanol, 50-100 mg iomeprol, and 50-100 mg Tween 20 are mixed.

Formulation 8—50-100 mg (0.05-0.11 mmole) rapamycin, 0.5-1.0 ml acetone,0.5-1.0 ml ethanol, 5-35 mg iomeprol, and 35-70 mg Tween 40 are mixed.

Example 2

5 PTCA balloon catheters (3 mm in diameter and 20 mm in length) arefolded with three wings under vacuum. The folded balloon under vacuum issprayed or dipped in a formulation (1-8) in example 1. The foldedballoon is then dried, sprayed or dipped again, dried again, and sprayedor dipped again until sufficient amount of drug on the balloon (3microgram per square mm) is obtained. The coated folded balloon is thenrewrapped and sterilized for animal testing.

Example 3

Drug coated balloon catheters and uncoated balloon catheters (ascontrol) are inserted into coronary arteries in pigs. The balloon isover dilated (1:1.2), and the inflated balloon is held in the vessel for60 seconds to release drug and additive, then deflated and withdrawnfrom the pig. The animals are angiographed after 3 days, 31 days, 3months, 6 months, 9 months and 12 months. The amount of drug in theartery tissues of the sacrificed animal is measured after 60 minutes, 3days, 31 days, 3 months, 6 months, 9 months and 12 months.

Example 4

5 coronary stents (3 mm in diameter and 18 mm in length) are spray ordip coated with the formulation (1-8) in example 1. The stents are thendried, sprayed or dipped again, and dried again until a sufficientamount of drug on the stent (3 microgram per square mm) is obtained. Thecoated stent is then crimped on PTCA balloon catheters (3 mm indiameters and 20 mm in length). The coated stents with balloon cathetersare then sterilized for animal testing.

Example 5

The drug coated stent and uncoated stent (as control) are inserted intocoronary arteries in pigs, then the balloon is over dilated (1:1.2). Thestent is implanted and drug and additive is released, and the balloon isdeflated and withdrawn from the pig. The animals are then angiographedafter 5, 30, 60 minutes, 3 days, 31 days, 3 months, 6 months, 9 monthsand 12 months. The amount of drug in the artery tissues of thesacrificed animal is measured 60 minutes, 1 day, 3 days, 31 days, 3months, 6 months, 9 months and 12 months.

Example 6

5 PTCA balloon catheters are sprayed or dipped in the formulation (1-8)in example 1, dried, and sprayed or dipped and dried again untilsufficient amount of drug on balloon is obtained (3 microgram per squaremm). A bare metal coronary stent (3 mm in diameter and 20 mm in length)is crimped on each coated balloon. The coated balloons with crimped baremetal stents are then wrapped and sterilized for animal test.

Example 7

The drug coated balloon with expandable bare metal stent of Examples 6and plain balloon with expandable bare metal stent (as control) areinserted into coronary arteries in pigs, and the balloon is over dilated(1:1.2). Stent is implanted, and the balloon is held inflated for 60seconds to release drug and additive, and the balloon is deflated andwithdrawn from the pig. The animals are then angiographed after 5, 30,60 minutes, 3 days, 31 days, 3 months, 6 months, 9 months and 12 months.The amount of drug in the artery tissues of the sacrificed animal ismeasured after 60 minutes, 1 day, 3 days, 31 days, 3 months, 6 months, 9months and 12 months.

Example 8

The drug coated balloon catheters and uncoated balloon catheters (ascontrol) are inserted via a bronchoscope into the pulmonary airway inpigs. The balloon is dilated, and the inflated balloon is held expandedin the lumen for 60 seconds to release drug and additive. The balloon isdeflated and withdrawn from the pig. The animals are then examinedbronchoscopically and tissues samples are taken for pathology andquantification of drug uptake after 3 days, 31 days, 3 months, 6 months,9 months and 12 months.

Example 9

The uncoated stent delivery catheters are inserted into the vascularlumen in pigs. The balloon is dilated, the stent is deployed, and thedeflated balloon is then withdrawn. The pharmaceutical formulation (1-8)of example 1 (10-100 ml) is injected (about 5-15 mg drug per pig) at thesite of stent implantation. The drug is then absorbed by injured tissue.The animals are then examined and tissues samples were taken forpathology.

Example 10

The diseased tissue (breast cancer or prostate or atheroma or stenosis)is removed surgically from a human body. The pharmaceutical formulation(1-8) of example 1 (10-100 ml) is then injected into or onto thesurgical cavities created by the surgical intervention (about 5-20 mgdrug). The local drug delivery included injection by long needle, guidecatheters, introducer shealth, drug infusion tube and other drugdelivery catheters. The drug is then absorbed by tissue at the targetsite.

Example 11

6 PTCA balloon catheters (3.5 and 3.0 mm in diameter and 20 mm inlength) are inflated at 1-3 atm. The inflated balloon is loaded with aformulation (1-8) in example 1. A sufficient amount of drug on theballoon (3 microgram per square mm) is obtained. The inflated balloon isfolded, and then dried. The coated folded balloon is then rewrapped andsterilized for animal testing.

The coated PTCA balloon catheter is inserted into a target site in thecoronary vasculature (LAD, LCX and RCA) of a 25-45 pound pig. Theballoon is inflated to about 12 atm. The overstretch ratio (the ratio ofballoon diameter to vessel diameter) is about 1.15-1.20. The drug isdelivered into the blood vessel during 30-60 seconds of inflation. Theballoon catheter is then deflated and is withdrawn from animal body. Thetarget blood vessel is harvested 0.25-24 hours after the procedure. Thedrug content in the target tissue and the residual drug remaining on theballoon is analyzed by tissue extraction and HPLC.

In some of these animal studies, a stent is crimped on the drug coatedballoon catheters prior to deployment. In chronic animal tests,angiography is performed before and after all interventions and at 28-35days after the procedure. Luminal diameters are measured and late lumenloss is calculated. Late lumen loss is the difference between theminimal lumen diameter measured after a period of follow-up time(usually weeks to months after an intervention, such as angioplasty andstent placement in the case of this example) and the minimal lumendiameter measured immediately after the intervention. Restenosis may bequantified by the diameter stenosis, which is the difference between themean lumen diameters at follow-up and immediately after the proceduredivided by the mean lumen diameter immediately after the procedure.

Example 12

6 PTCA balloon components (3.5 and 3.0 mm in diameter and 20 mm inlength) are loaded with formulation 1 provided in Example 1. Asufficient amount of drug (3 μg/mm²) is obtained on the balloon surface.The balloon is dried.

A formulation for a top coating layer is then prepared. The formulationof the top coating layer is paclitaxel, and one additive chosen fromTween 20, Tween 80, polypropylene glycol-425 (PPG-425), and polypropylglycol-1000 (PPG-1000), in acetone. The balloon surface of the controlcatheters is only loaded with formulation 1. 25-50 mg of the top coatingformulation (about 50% of paclitaxel by weight) in acetone is coatedover the formulation 1 coating layer on the other balloon surfaces. Thecoated balloons are dried for drug releasing testing in vitro.

The releasing experiment is designed to test how much drug is lostduring balloon inflation. Each of the coated balloons is inflated to 12atm. in 1% BSA solution at 37° C. for 2 minutes. The drug, additive andtop coating are released. The residual drug on the balloon catheters isanalyzed by HPLC. The top coating layer reduces drug loss in the testsin vitro during inflation of the balloon components.

What is claimed is:
 1. A balloon catheter for delivering a therapeuticagent to target site in a blood vessel, the balloon catheter comprising:a coating layer overlying an exterior surface of a balloon, the coatinglayer comprising a therapeutic agent, a contrast agent, and at least onefirst additive, wherein: the therapeutic agent is selected from thegroup consisting of paclitaxel, rapamycin, and combinations thereof; andthe contrast agent is selected from the group consisting of iobitridol,iohexol, iomeprol, iopamidol, iopentol, iopromide, ioversol, ioxilan,iotrolan, iodixanol, and ioxaglate; and the at least one first additivecomprises a PEG fatty ester selected from the group consisting of PEGlaurates, PEG oleates, PEG stearates, PEG glyceryl laurates, PEGglyceryl oleates, PEG glyceryl stearates, PEG sorbitan monolaurates, PEGsorbitan monooleates, PEG sorbitan stearates, PEG sorbitan laurates, PEGsorbitan oleates, PEG sorbitan palmitates, and combinations thereof. 2.The balloon catheter of claim 1, wherein the at least one first additiveis selected from the group consisting of PEG-20 sorbitan monolaurate,PEG-20 sorbitan monopalmitate, PEG-20 sorbitan monostearate, PEG-20sorbitan monooleate, and combinations thereof.
 3. The balloon catheterof claim 1, wherein the contrast agent is selected from the groupconsisting of iopromide, ioversol, and iomeprol.
 4. The balloon catheterof claim 1, wherein: the contrast agent is selected from the groupconsisting of iopromide, ioversol, and iomeprol; and the at least onefirst additive is selected from the group consisting of PEG-20 sorbitanmonolaurate, PEG-20 sorbitan monopalmitate, PEG-20 sorbitanmonostearate, PEG-20 sorbitan monooleate, and combinations thereof. 5.The balloon catheter of claim 4, wherein: the therapeutic agent ispaclitaxel; the contrast agent is iopromide; and the at least one firstadditive is PEG-20 sorbitan monolaurate.
 6. The balloon catheter ofclaim 4, wherein: the therapeutic agent is paclitaxel; the contrastagent is iopromide; and the at least one first additive is PEG-20sorbitan monopalmitate.
 7. The balloon catheter of claim 4, wherein: thetherapeutic agent is rapamycin; the contrast agent is iopromide; and theat least one first additive is PEG-20 sorbitan monolaurate.
 8. Theballoon catheter of claim 4, wherein: the therapeutic agent israpamycin; the contrast agent is iopromide; and the at least one firstadditive is PEG-20 sorbitan monopalmitate.
 9. The balloon catheter ofclaim 4, wherein: the therapeutic agent is paclitaxel; the contrastagent is ioversol; and the at least one first additive is PEG-20sorbitan monolaurate.
 10. The balloon catheter of claim 4, wherein: thetherapeutic agent is paclitaxel; the contrast agent is ioversol; and theat least one first additive is PEG-20 sorbitan monopalmitate.
 11. Theballoon catheter of claim 4, wherein: the therapeutic agent israpamycin; the contrast agent is iomeprol; and the at least one firstadditive is PEG-20 sorbitan monolaurate.
 12. The balloon catheter ofclaim 4, wherein: the therapeutic agent is rapamycin; the contrast agentis iomeprol; and the at least one first additive is PEG-20 sorbitanmonopalmitate.
 13. The balloon catheter of claim 1, wherein the coatinglayer further comprises a hydrophilic second additive selected from thegroup consisting of polyglyceryl-10 oleate,p-isononylphenoxypolyglycidol, L-ascorbic acid, D-glucoascorbic acid,tromethamine, triethanolamine, diethanolamine, meglumine, glucamine,glucoheptonic acid, glucomic acid, hydroxyl ketone, hydroxyl lactone,gluconolactone, glucoheptonolactone, glucooctanoic lactone, gulonic acidlactone, mannoic lactone, ribonic acid lactone, lactobionic acid,glucosamine, glutamic acid, benzyl alcohol, benzoic acid, hydroxybenzoicacid, propyl 4-hydroxybenzoate, lysine acetate, gentisic acid,lactobionic acid, lactitol, sorbitol, glucose, ribose, arabinose,lyxose, xylose, fructose, mannose, glucitol, glucopyranose phosphate,sinapic acid, vanillic acid, vanillin, methyl paraben, propyl paraben,diethylene glycol, triethylene glycol, tetraethylene glycol, xylitol,2-ethoxyethanol, galactose, glucose, mannose, xylose, sucrose, lactose,maltose, cyclodextrin, sorbitol, (2-hydroxypropyl)-cyclodextrin,acetaminophen, ibuprofen, retinoic acid, lysine acetate, gentisic acid,catechin, catechin gallate, tiletamine, ketamine, propofol, lacticacids, acetic acid, and salts of any of the foregoing organic acids oramines.
 14. The balloon catheter of claim 13, wherein the hydrophilicsecond additive is selected from the group consisting of polyglyceryl-10oleate, p-isononylphenoxypolyglycidol, gluconolactone, sorbitol,lactobionic acid, and N-octanoyl-N-methylglucamine.
 15. The ballooncatheter of claim 13, wherein the hydrophilic second additive isselected from the group consisting of gluconolactone, sorbitol,lactobionic acid, N-octanoyl-N-methylglucamine, and combinationsthereof.
 16. The balloon catheter of claim 13, wherein the hydrophilicsecond additive is selected from the group consisting of gluconolactone,sorbitol, and combinations thereof.
 17. The balloon catheter of claim13, wherein the at least one first additive is PEG-20 sorbitanmonolaurate and the hydrophilic second additive is selected from thegroup consisting of gluconolactone, sorbitol, lactobionic acid,N-octanoyl-N-methylglucamine, and combinations thereof.
 18. The ballooncatheter of claim 13, wherein the at least one first additive is PEG-20sorbitan monolaurate, and the hydrophilic second additive is selectedfrom the group consisting of gluconolactone, sorbitol and combinationsthereof.
 19. The balloon catheter of claim 13, wherein the therapeuticagent is paclitaxel, the at least one first additive is PEG-20 sorbitanmonolaurate, and the hydrophilic second additive is selected from thegroup consisting of gluconolactone, sorbitol, and combinations thereof.20. The balloon catheter of claim 13, wherein the therapeutic agent ispaclitaxel, the at least one first additive is PEG-20 sorbitanmonolaurate, and the hydrophilic second additive is gluconolactone. 21.The balloon catheter of claim 13, wherein the therapeutic agent ispaclitaxel, the at least one first additive is PEG-20 sorbitanmonolaurate, and the hydrophilic second additive is sorbitol.
 22. Theballoon catheter of claim 1, wherein the coating layer further comprisesa hydrophobic second additive selected from the group consisting ofsoybean oil, vegetable oil, flower oil, animal oil, coconut oil, palmoil, olive oil, peanut oil, fish oil, butanoic acid, hexanoic acid,octanoic acid, decanoic acid, dodecanoic acid, tetradecanoic acid,hexadecanoic acid, octadecanoic acid, octadecatrienoic acid, eicosanoicacid, eicosenoic acid, eicosatetraenoic acid, eicosapentaenoic acid,docosahexaenoic acid, tocotrienol, butyric acid, caproic acid, caprylicacid, capric acid, lauric acid, myristic acid, palmitic acid,palmitoleic acid, stearic acid, oleic acid, vaccenic acid, linoleicacid, alpha-linolenic acid, gamma-linolenic acid, behenic acid, erucicacid, lignoceric acid, natural or synthetic phospholipids,monoacylglycerols, diacylglycerols, triacylglycerols, cardiolipin,phosphatidylglycerol, phosphatidic acid, phosphatidylcholine, alphatocoferol, phosphatidylethanolamine, sphingomyelin, phosphatidylserine,phosphatidylinositol, dimyristoylphosphatidylcholine,dioleoylphosphatidylcholine, dipalmitoylphosphatidylcholine,distearoylphosphatidylcholine, phosphatidylethanolaminesphosphatidylglycerols, sphingolipids, prostaglandins, gangliosides,neobee, and niosomes.
 23. The balloon catheter of claim 22, wherein thehydrophobic second additive is selected from the group consisting ofphosphatidylcholine, phosphatidylethanolamine, anddimyristoylphosphatidylcholine.
 24. The balloon catheter of claim 1,wherein the coating layer further comprises a second therapeutic agentselected from the group consisting of beta-lapachone and biologicallyactive vitamin D.
 25. The balloon catheter of claim 1, wherein thecoating layer consists essentially of the therapeutic agent, thecontrast agent, and the at least one first additive.
 26. The ballooncatheter of claim 1, wherein the catheter further comprises adimethylsulfoxide solvent layer overlying the surface of the coatinglayer.
 27. The balloon catheter of claim 1, wherein the concentration ofthe therapeutic agent in the coating layer is from 1 μg/mm² to 20μg/mm².
 28. The balloon catheter of claim 1, wherein the concentrationof the therapeutic agent in the coating layer is from 2 μg/mm² to 10μg/mm².
 29. The balloon catheter of claim 1, wherein the ratio by weightof the at least one first additive to the therapeutic agent in thecoating layer is from about 0.1 to
 5. 30. The balloon catheter of claim1, wherein the ratio by weight of the at least one first additive to thetherapeutic agent in the coating layer is from about 0.5 to
 2. 31. Theballoon catheter of claim 1, wherein the ratio by weight of the at leastone first additive to the therapeutic agent in the coating layer is fromabout 0.8 to 1.2.
 32. The balloon catheter of claim 1, wherein thecoating layer does not include an oil or lipid.
 33. The balloon catheterof claim 1, wherein the therapeutic agent is not enclosed in micelles orencapsulated in polymer particles.
 34. The balloon catheter of claim 1,wherein the coating layer does not include a polymer.
 35. The ballooncatheter of claim 1, wherein the balloon catheter is a perfusion ballooncatheter, a cutting balloon catheter, or a scoring balloon catheter. 36.The balloon catheter of claim 1, further comprising a top layeroverlying the surface of the coating layer, wherein the top layercomprises a top-layer additive selected from the group consisting ofPEG-20 sorbitan monolaurate, PEG-20 sorbitan monopalmitate, PEG-20monostearate, PEG-20 sorbitan monooleate, polyglyceryl oleate,polyethylene oxide, polyethylene glycol, polyvinyl pyrrolidone,L-ascorbic acid and its salts, D-glucoascorbic acid and its salts,tromethamine, triethanolamine, diethanolamine, meglumine, glucamine,amine alcohols, glucoheptonic acid, gluconic acid, hydroxy ketones,hydroxy lactones, gluconolactone, glucoheptonolactone, glucooctanoiclactone, gulonic acid lactone, mannoic lactone, ribonic acid lactone,lactobionic acid, glucosamine, glutamic acid, benzyl alcohol, benzoicacid, hydroxybenzoic acid, propyl 4-hydroxybenzoate, lysine acetatesalt, gentisic acid, lactitol, sinapic acid, vanillic acid, vanillin,methyl paraben, propyl paraben, sorbitol, cyclodextrin,(2-hydroxypropyl)-cyclodextrin, acetaminophen, ibuprofen, retinoic acid,lysine acetate, gentisic acid, catechin, catechin gallate, tiletamine,ketamine, propofol, and combinations thereof.
 37. The balloon catheterof claim 36, wherein the top-layer additive is selected from the groupconsisting of PEG-20 sorbitan monolaurate, PEG-20 sorbitanmonopalmitate, PEG-20 monostearate, PEG-20 sorbitan monooleate,polyglyceryl oleate, polyethylene oxide, polyethylene glycol, andpolyvinyl pyrrolidone.
 38. The balloon catheter of claim 37, wherein thetop layer further comprises a therapeutic agent selected from the groupconsisting of paclitaxel, rapamycin, and combinations thereof.
 39. Theballoon catheter of claim 38, wherein the concentration of thetherapeutic agent in the top layer is lower than the concentration ofthe therapeutic agent in the coating layer.